Benzamidine derivatives and their use as anti-coagulants

ABSTRACT

This invention is directed to benzamidine derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.

FIELD OF THE INVENTION

[0001] The present invention is directed to benzamidine derivatives andtheir pharmaceutically acceptable salts, which inhibit the enzyme,factor Xa, thereby being useful as anti-coagulants. It also relates topharmaceutical compositions containing the derivatives or theirpharmaceutically acceptable salts, and methods of their use.

BACKGROUND OF THE INVENTION

[0002] Factor Xa is a member of the trypsin-like serine protease classof enzymes. A one-to-one binding of factors Xa and Va with calcium ionsand phospholipid forms the prothrombinase complex which convertsprothrombin to thrombin. Thrombin, in turn, converts fibrinogen tofibrin which polymerizes to form insoluble fibrin.

[0003] In the coagulation cascade, the prothrombinase complex is theconvergent point of the intrinsic (surface activated) and extrinsic(vessel injury-tissue factor) pathways (Biochemistry (199 1), Vol. 30,p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of thecoagulation cascade has been refined further with the discovery of themode of action of tissue factor pathway inhibitor (TFPI) (Seminars inHematology (1992), Vol. 29, pp. 159-161). TFPI is a circulatingmulti-domain serine protease inhibitor with three Kunitz-like serpindomains which competes with factor Va for free factor Xa. Once formed,the binary complex of factor Xa and TFPI becomes a potent inhibitor ofthe factor Vlla and tissue factor complex.

[0004] Factor Xa can be activated by two distinct complexes, by tissuefactor-VIIa complex on the “Xa burst” pathway and by the factorIXa-VIIIA complex (TENase) of the “sustained Xa” pathway in thecoagulation cascade. After vessel injury, the “Xa burst” pathway isactivated via tissue factor (TF). Up regulation of the coagulationcascade occurs via increased factor Xa production via the “sustained Xa”pathway. Down regulation of the coagulation cascade occurs with theformation of the factor Xa-TFPI complex, which not only removes factorXa but also inhibits further factor formation via the “Xa burst”pathway. Therefore, the coagulation cascade is naturally regulated byfactor Xa.

[0005] The primary advantage of inhibiting factor Xa over thrombin inorder to prevent coagulation is the focal role of factor Xa versus themultiple functions of thrombin. Thrombin not only catalyzes theconversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V toVa, and factor XI to XIa, but also activates platelets, is a monocytechemotactic factor, and mitogen for lymphocytes and smooth muscle cells.Thrombin activates protein C, the in vivo anti-coagulant inactivator offactors Va and VIIIa, when bound to thrombomodulin. In circulation,thrombin is rapidly inactivated by antithrombin III (ATIII) and heparincofactor II (HCII) in a reaction which is catalyzed by heparin or otherproteolycan-associated glycosaminoglycans, whereas thrombin in tissuesis inactivated by the protease, nexin. Thrombin carries out its multiplecellular activation functions through a unique “tethered ligand”thrombin receptor (Cell (1991), Vol.64, p. 1057), which requires thesame anionic binding site and active site used in fibrinogen binding andcleavage and by thrombomodulin binding and protein C activation. Thus, adiverse group of in vivo molecular targets compete to bind thrombin andthe subsequent proteolytic events will have very different physiologicalconsequences depending upon which cell type and which receptor,modulator, substrate or inhibitor binds thrombin.

[0006] Published data with the proteins antistasin and tickanti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors areefficacious anti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67,pp. 371-376; and Science (1990), Vol. 248, pp. 593-596).

[0007] The active site of factor Xa can be blocked by either amechanism-based or a tight binding inhibitor (a tight binding inhibitordiffers from a mechanism-based inhibitor by the lack of a covalent linkbetween the enzyme and the inhibitor). Two types of mechanism-basedinhibitors are known, reversible and irreversible, which aredistinguished by ease of hydrolysis of the enzyme-inhibitor link(Thrombosis Res (1992), Vol. 67, pp. 221-231; and Trends Pharmacol. Sci.(1987), Vol. 8, pp. 303-307). A series of guanidino compounds areexamples of tight-binding inhibitors (Thrombosis Res. (1980), Vol. 19,pp.339-349). Arylsulfonyl-arginine-piperidinecarboxylic acid derivativeshave also been shown to be tight-binding inhibitors of thrombin(Biochem. (1984), Vol. 23, pp. 85-90), as well as a series ofarylamidine-containing compounds, including 3-amidinophenylarylderivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) andbis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp.545-548). However, these compounds demonstrate poor selectivity forfactor Xa.

[0008] Related Disclosures

[0009] European Published Patent Application 0 540 051 (Nagahara et al.)describes aromatic amidine derivatives which are stated to be capable ofshowing a strong anticoagulant effect through reversible inhibition offactor Xa.

[0010] The synthesis of α,α′-bis(amidinobenzylidene)cycloalkanones andα,α′-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977),Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as beingserine protease inhibitors.

SUMMARY OF THE INVENTION

[0011] This invention is directed to compounds or their pharmaceuticallyacceptable salts which inhibit human factor Xa and are therefore usefulas pharmacological agents for the treatment of disease-statescharacterized by thrombotic activity.

[0012] Accordingly, in one aspect, this invention provides compoundsselected from the group consisting of the following formulae:

[0013] wherein

[0014] A is —C(R¹¹)═ or —N═;

[0015] Z¹ and Z² are independently —O—, —N(R⁸)—, —S—, or —OCH₂—;

[0016] R¹ and R³ are independently hydrogen, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, nitro, —N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹,—C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸,—N(R⁸)S(O)₂R¹², or —N(R⁸)C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹;

[0017] R² is hydrogen; halo; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸;—C(O)N(R⁸)R⁹;

[0018] —N(R⁸)R⁹; —C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3);—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);—N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3);—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

[0019] or R² is aryloxy (optionally substituted by one or moresubstituents independently selected from the group consisting of —OR⁸,—C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl));

[0020] or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl);

[0021] or R² is 1-piperazinoyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, carboxy,—C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);

[0022] or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy,—C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);

[0023] or R² is (3,4)-piperidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of alkylcarbonyl,carboxy, —C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, and tetrazolylalkyl);

[0024] or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkoxycarbonyl, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonylalkyl andaralklyl);

[0025] or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl and alkoxycarbonylalkyl);

[0026] R⁴ and R⁷ are independently hydrogen, halo, alkyl, nitro, —OR⁸,—C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹, —N(H)C(O)R⁸, or —N(H)S(O)₂R¹²;

[0027] R⁵ is —C(NH)NH₂, —C(NH)N(H)OR⁸, —C(NH)N(H)C(O)OR¹²,—C(NH)N(H)S(O)₂R¹², —C(NH)N(H)C(O)N(R⁸)R⁹, or —C(NH)N(H)C(O)R⁸;

[0028] R⁶ is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido,guanidino, —OR⁸, —C(NH)NH₂, —C(NH)NHOH, —C(O)R¹⁰, —(CH₂)_(m)C(O)N(R⁸)R⁹(where m is 0 to 3), —CH(OH)C(O)N(R⁸)R⁹, —(CH₂)_(m)N(R⁸)R⁹ (where m is 0to 3), —(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3), —N(H)C(O)R⁸,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

[0029] each R⁸ and R⁹ is independently hydrogen, alkyl, aryl, oraralkyl;

[0030] R¹⁰ is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl,4-morpolinyl, 4-piperazinyl, 4-(N-methyl)piperazinyl, or piperidin-1-yl;

[0031] R¹¹ is hydrogen, alkyl or halo; and

[0032] R¹² is alkyl, aryl or aralkyl;

[0033] or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, this invention provides compositions useful intreating a human having a disease-state characterized by thromboticactivity, which composition comprises a therapeutically effective amountof a compound of the invention as described above, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

[0035] In another aspect, this invention provides a method of treating ahuman having a disease-state characterized by thrombotic activity, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

[0036] In another aspect, this invention provides a method of treating ahuman having a disease-state alleviated by the inhibition of factor Xa,which method comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

[0037] In another aspect, this invention provides a method of inhibitinghuman factor Xa in vitro or in vivo by the administration of a compoundof the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0038] Definitions

[0039] As used in the specification and appended claims, unlessspecified to the contrary, the following terms have the meaningindicated:

[0040] “Halo” refers to bromo, chloro or fluoro.

[0041] “Aminocarbonyl” refers to the radical —C(O)NH₂.

[0042] “Amidino” refers to the radical —C(NH)NH₂.

[0043] “Benzamidine” refers to a phenyl radical substituted by anamidino radical.

[0044] “Carboxy” refers to the radical —C(O)OH.

[0045] “Dimethylaminocarbonyl” refers to the radical —C(O)N(CH₃)₂.

[0046] “Alkyl” refers to a straight or branched chain monovalent ordivalent radical consisting solely of carbon and hydrogen, containing nounsaturation and having from one to six carbon atoms, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

[0047] “Alkenyl” refers to a straight or branched chain monovalent ordivalent radical consisting solely of carbon and hydrogen, containing atleast one double bond and having from one to six carbon atoms, e.g.,ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and thelike.

[0048] “Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

[0049] “Haloalkoxy” refers to a radical of the formula —OR_(b) whereinR_(b) is haloalkyl as defined above, e. g. , trifluoromethoxy,difluoromethoxy, trichloromethoxy, 2-trifluoroethoxy,1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy,1-bromomethyl-2-bromoethoxy, and the like.

[0050] “Aryl” refers to a phenyl or naphthyl radical optionallysubstituted by halo, alkyl, alkoxy, amino, nitro or carboxy.

[0051] “Aralkyl” refers to a radical of the formula R_(a)R_(c) whereR_(a) is alkyl as defined above and R_(c) is aryl as defined above,e.g., benzyl.

[0052] “Aryloxy” refers to a radical of the formula —OR_(c) where R_(c)is phenyl or naphthyl, e.g., phenoxy and naphthoxy.

[0053] “Alkoxy” refers to a radical of the formula —OR_(a) where R_(a)is alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy,1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy(t-butoxy), and the like.

[0054] “Alkanol” refers to a branched or unbranched aliphatichydrocarbon of 1 to 6 carbons wherein one hydroxyl radical is attachedthereto, e.g., methanol, ethanol, isopropanol, and the like.

[0055] “Aminocarbonylalkyl” refers to a radical of the formula—R_(a)C(O)NH₂ wherein R_(a) is alkyl as defined above, eg.,aminocarbonylmethyl, 2-aminocarbonylethyl, 3-aminocarbonylpropyl,1,1-dimethyl-2-aminocarbonylethyl, and the like.

[0056] “(Alkylamino)carbonylalkyl” refers to a radical of the formula—R_(a)C(O)N(H)R_(a) wherein each R_(a) is the same or different and isalkyl as defined above, e.g., (methylamino)carbonylmethyl,2-(ethylamino)oarbonylethyl, 3-(methylamino)-carbonylpropyl,1,1-dimethyl-2-(ethylamino)carbonylethyl, and the like.

[0057] “(Dialkylamino)carbonylalkyl” refers to a radical of the formula—R_(a)C(O)N(R_(a))₂ wherein each R_(a) is the same or different and isalkyl as defined above, eg., (dimethylamino)carbonylmethyl,2-(diethylamino)carbonylethyl, 3-(dimethylamino)carbonylpropyl,1,1-dimethyl-2-(diethylamino)carbonylethyl, and the like.

[0058] “(Arylamino)carbonylalkyl” refers to a radical of the formula—R_(a)C(O)N(H)R_(c) wherein R_(a) is alkyl as defined above and R_(c) isaryl as defined above, e.g., phenylaminocarbonylmethyl,2-phenylaminocarbonylethyl, 3-phenylaminocarbonylpropyl,1,1-dimethyl-2-phenylaminocarbonylethyl, and the like.

[0059] “(Aralkylaminocarbonylalkyl” refers to a radical of the formula—R_(a)C(O)N(H)R_(c) wherein R_(a) is alkyl as defined above and R_(d) isaralkyl as defined above, e.g., benzylaminocarbonylmethyl,2-benzylaminocarbonylethyl;3-benzylaminocarbonylpropyl,1,1-dimethyl-2-benzylaminocarbonylethyl,and the like.

[0060] “Alkoxycarbonylalkenyl” refers to a radical of the formula—R_(e)C(O)OR_(a) wherein R_(a) is lower alkyl as defined above and R_(e)is alkenyl as defined above, e.g., 2-methoxycarbonylethenyl,3-methoxycarbonyprop-1-enyl, 2-ethoxycarbonylethenyl, and the like.

[0061] “Carboxyalkenyl” refers to a radical of the formula —R_(e)C(O)OHwhere R_(e) is alkenyl as defined above, e.g., 2-carboxyethenyl,3-carboxyprop-1-enyl, 4-carboxybut-1-enyl, and the like.

[0062] “Aminocarbonylalkenyl” refers to a radical of the formula—R_(e)C(O)NH₂ wherein R_(e) is alkenyl as defined above, e.g.,2-aminocarbonylethenyl, 3-aminocarbonylprop-1-enyl,1-methyl-2-aminocarbonylethenyl, and the like.

[0063] “(Alkylamino)carbonylalkenyl” refers to a radical of the formula—R_(e)C(O)N(H)R_(a) wherein R_(a) is alkyl as defined above and R_(e) isalkenyl as defined above, e.g., 2-(ethylamino)carbonylethenyl,3-(methylamino)carbonylprop-1-enyl,1-methyl-2-(ethylamino)carbonylethenyl, and the like.

[0064] “(Dialkylamino)carbonylalkenyl” refers to a radical of theformula —R_(e)C(O)N(R_(a))₂ wherein each R_(a) is the same or differentand is as defined above and R_(e) is alkenyl as defined above, e.g.,2-(diethylamino)carbonylethenyl, 3-(dimethylamino)carbonylprop-1-enyl,1-methyl-2-(diethylamino)carbonylethenyl, and the like.

[0065] “(Arylamino)carbonylalkenyl” refers to a radical of the formula—R_(e)C(O)N(H)R_(c) wherein R_(c) is aryl as defined above and Re isalkenyl as defined above, e.g., 2-(phenylamino)carbonylethenyl,3-(phenylamino)carbonylprop-1-enyl,1-methyl-2-(phenylamino)carbonylethenyl, and the like.

[0066] “(Aralkylamino)carbonylalkenyl” refers to a radical of theformula —R_(e)C(O)N(H)R_(d) wherein R_(d) is aralkyl as defined aboveand Re is alkenyl as defined above, e.g.,2-(benzylamino)carbonylethenyl, 3-(benzylamino)carbonylprop-1-enyl,1-methyl-2-(benzylamino)carbonylethenyl, and the like.

[0067] “(Hydroxyalkoxy)carbonyl” refers to a radical of the formula—C(O)OR_(a) wherein R_(a) is alkyl as defined above substituted by ahydroxy radical, e.g., 2-(hydroxy)ethoxycarbonyl,3-(hydroxy)propoxycarbonyl, 5-(hydroxy)pentoxycarbonyl, and the like.

[0068] “(Alkoxy)alkoxycarbonyl” refers to a radical of the formula—C(O)OR_(a)OR_(a) wherein each R_(a) is the same or different and isalkyl as defined above, e.g., 2-(methoxy)ethoxycarbonyl,3-(methoxy)propoxycarbonyl, 5-(ethoxy)pentoxycarbonyl, and the like.

[0069] “(Hydroxyalkoxy)alkoxycarbonyl” refers to a radical of theformula —C(O)OR_(a)OR_(a), wherein each R_(a) is the same or differentand is alkyl as defined above, and the terminal R_(a) radical issubstituted by a hydroxy radical, e.g.,2-(2-hydroxyethoxy)ethoxycarbonyl, 2-(3-hydroxypropoxy)ethoxycarbonyl,and the like.

[0070] “((Alkoxy)alkoxy)alkoxycarbonyl” refers to a radical of theformula —C(O)OR_(a)OR_(a)OR_(a) where each R_(a) is the same ordifferent and is alkyl as defined above, e.g.,2-(2-(methoxy)ethoxy)ethoxycarbonyl,3-(2-(methoxy)ethoxy)propoxycarbonyl,4-(3-ethoxy)propoxy)butoxycarbonyl, and the like.

[0071] “Haloalkoxycarbonyl” refers to a radical of the formula—C(O)OR_(b) wherein R_(b) is haloalkyl as defined above, e.g.,trifluoromethoxycarbonyl, difluoromethoxycarbonyl,trichloromethoxycarbonyl,2-trifluoroethoxycarbonyl,1-fluoromethyl-2-fluoro-ethoxycarbonyl,3-bromo-2-fluoropropoxycarbonyl, 1-bromomethyl-2-bromoethoxy-carbonyl,and the like.

[0072] “Carboxyalkyl” refers to a radical of the formula —R_(a)C(O)OHwhere R_(a) is alkyl as defined above, e.g., carboxymethyl,2-carboxyethyl, 3-carboxypropyl, and the like.

[0073] “Alkoxycarbonyl” refers to a radical of the formula —C(O)OR_(a)wherein R_(a) is alkyl as defined above, e.g., methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, and the like.

[0074] “Alkoxycarbonylalkyl” refers to a radical of the formula—R_(a)C(O)OR_(a) wherein each R_(a) is the same or different and isalkyl as defined above, e.g., methoxycarbonylethyl, ethoxycarbonylethyl,t-butoxycarbonylethyl, and the like.

[0075] “Morpholin-4-ylalkyl” refers to a radical of the formula—R_(a)R_(f) where R_(a) is alkyl as defined above and R_(f) is amorpholin-4-yl radical, e.g., morpholin-4-ylmethyl, morpholin-4-ylethyl,and the like.

[0076] “4-morpholinoyl” refers to a radical of the formula —C(O)R_(f)where R_(f) is a morpholin-4-yl radical.

[0077] “(3,4)-Piperidinyloxy” refers to a radical of the formula —OR_(g)where R_(g) is a piperidinyl radical attached to the oxygen atom ateither the 3- or 4-position.

[0078] “3-Tetrahydrofuranyloxy” refers to the radical of the formula—OR_(h) where R_(h) is a tetrahydrofuranyl radical attached to theoxygen atom at the 3-position.

[0079] “3-Pyrrolidinyloxy” refers to the radical of the formula —OR_(i)where R_(i) is a pyrrolidinyl radical attached to the oxygen atom at the3-position.

[0080] “1-Piperazinoyl” refers to the radical of the formula —C(O)R_(j)where R_(j) is piperazin-1-yl.

[0081] “1-Piperidinoyl” refers to the radical of the formula —C(O)R_(k)where R_(k) is piperidin-1-yl.

[0082] “1-Pyrrolidinoyl” refers to the radical of the formula —C(O)R_(m)where R_(m) is pyrrolidin-1-yl.

[0083] “(1,2)-Imidazolyl” refers to an imidazolyl radical attached ateither the 1- or 2-position.

[0084] “(1,2)-Imidazolinyl” refers to a 4,5-dihydroimidazolyl radicalattached at either the 1- or the 2-position.

[0085] “DMSO” refers to dimethyl sulfoxide.

[0086] “HPLC” refers to high performance liquid chromatography.

[0087] “Optional” or “optionally” means that the subsequently describedevent of circumstances may or may not occur, and that the descriptionincludes instances where said event or circumstance occurs and instancesin which it does not. For example, “optionally substituted aryl” meansthat the aryl radical may or may not be substituted and that thedescription includes both substituted aryl radicals and aryl radicalshaving no substitution.

[0088] “Pharmaceutically acceptable salt” includes both acid and baseaddition salts.

[0089] “Pharmaceutically acceptable acid addition salt” refers to thosesalts which retain the biological effectiveness and properties of thefree bases, which are not biologically or otherwise undesirable, andwhich are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, and organic acids such as acetic acid, trifluoroacetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike.

[0090] “Pharmaceutically acceptable base addition salt” refers to thosesalts which retain the biological effectiveness and properties of thefree acids, which are not biologically or otherwise undesirable. Thesesalts are prepared from addition of an inorganic base or an organic baseto the free acid. Salts derived from inorganic bases include, but arenot limited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts arethe ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine,procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline and caffeine.

[0091] “Therapeutically effective amount” refers to that amount of acompound of formula (I) which, when administered to a human in needthereof, is sufficient to effect treatment, as defined below, fordisease-states characterized by thrombotic activity. The amount of acompound of formula (I) which constitutes a “therapeutically effectiveamount” will vary depending on the compound, the disease-state and itsseverity, and the age of the human to be treated, but can be determinedroutinely by one of ordinary skill in the art having regard to his ownknowledge and to this disclosure.

[0092] “Treating” or “treatment” as used herein cover the treatment of adisease-state in a human, which disease-state is characterized bythrombotic activity; and include:

[0093] (i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it;

[0094] (ii) inhibiting the disease-state, i.e., arresting itsdevelopment; or

[0095] (iii) relieving the disease-state, ire., causing regression ofthe disease-state.

[0096] The yield of each of the reactions described herein is expressedas a percentage of the theoretical yield.

[0097] The compounds of the invention, or their pharmaceuticallyacceptable salts, may have asymmetric carbon atoms in their structure.The compounds of the invention and their pharmaceutically acceptablesalts may therefore exist as single stereoisomers, racemates, and asmixtures of enantiomers and diastereomers. All such singlestereoisomers, racemates and mixtures thereof are intended to be withinthe scope of this invention.

[0098] The nomenclature used herein is a modified form of the I.U.P.A.C.system wherein the compounds of the invention are named as derivativesof benzamidine. For example, a compound of the invention selected fromformula (I), i.e.,

[0099] wherein A is —N═, Z¹ and Z² are both —O—, R¹ and R³ are bothfluoro, R² is methyl, R⁴ is methoxy, R⁵ is —C(NH)NH₂. R⁶ isdimethylamino, and R⁷ is hydrogen, that is, a compound of the followingformula:

[0100] is named herein as4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxylbenzamidine.

[0101] Utility and Administration

[0102] A. Utility

[0103] The compounds of the invention are inhibitors of factor Xa andtherefore useful in disease-states characterized by thrombotic activitybased on factor Xa's role in the coagulation cascade (see Background ofthe Invention above). A primary indication for the compounds isprophylaxis for long term risk following myocardial infarction.Additional indications are prophylaxis of deep vein thrombosis (DVT)following orthopedic surgery or prophylaxis of selected patientsfollowing a transient ischemic attack. The compounds of the inventionmay also be useful for indications in which coumadin is currently used,such as for DVT or other types of surgical intervention such as coronaryartery bypass graft and percutaneous transluminal coronary angioplasty.The compounds are also useful for the treatment of thromboticcomplications associated with acute promyelocytic leukemia, diabetes,multiple myelomas, disseminated intravascular coagulation associatedwith septic shock, purpura fulminanas associated infection, adultrespiratory distress syndrome, unstable angina, and thromboticcomplications associated with aortic valve or vascular prosthesis. Thecompounds are also useful, for prophylaxis for thrombotic diseases, inparticular in patients who have a high risk of developing such disease.

[0104] In addition, the compounds of the invention are useful as invitro diagnostic reagents for selectively inhibiting factor Xa withoutinhibiting other components of the coagulation cascade.

[0105] B. Testing

[0106] The primary bioassays used to demonstratethe inhibitory effect ofthe compounds of the invention on factor Xa are simple chromogenicassays involving only serine protease, the compound of the invention tobe tested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol.16, pp. 245-254). For example, four tissue human serine proteases can beused in the primary bioassay, free factor Xa, prothrombinase, thrombin(IIa) and tissue plasminogen activator (tPA). The assay for tPA has beensuccessfully used before to demonstrate undesired side effects in theinhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993),Vol. 36, pp. 314-319). Another bioassay useful in demonstrating theutility of the compounds of the invention in inhibiting factor Xademonstrates the potency of the compounds against free factor Xa incitrated plasma. For example, the anticoagulant efficacy of thecompounds of the invention will be tested using either the prothrombintime (PT), or activated partial thromboplastin time (aPTT) whileselectivity of the compounds is checked with thethrombin clotting time(TCT) assay. Correlation of the K_(i) in the primary enzyme assay withthe K_(i) for free factor Xa in citrated plasma will screen againstcompounds which interact with or are inactivated by other plasmacomponents. Correlation of the K_(i) with the extension of the PT is anecessary in vitro demonstration that potency in the free factor Xainhibition assay translates into potency in a clinical coagulationassay. In addition, extension of the PT in citrated plasma can be usedto measure duration of action in subsequent pharmacodynamic studies.

[0107] For further information on assays to demonstratethe activity ofthe compounds of the invention, see R. Lottenberg et al., Methods inEnzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., ThrombosisResearch (1980), Vol. 19, pp. 579-588.

[0108] C. General Administration

[0109] Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally,topically, transdermally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

[0110] Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. Preferably, the composition will be about 5%to 75% by weight of a compound(s) of the invention, or apharmaceutically acceptable salt thereof, with the rest being suitablepharmaceutical excipients.

[0111] The preferred route of administration is oral, using a convenientdaily dosage regimen which can be adjusted according to the degree ofseverity of the disease-state to be treated. For such oraladministration, a pharmaceutically acceptable composition containing acompound(s) of the invention, or a pharmaceutically acceptable saltthereof, is formed by the incorporation of any of the normally employedexcipients, such as, for example, pharmaceutical grades of mannitol,lactose, starch, pregelatinized starch, magnesium stearate, sodiumsaccharine, talcum, cellulose ether derivatives, glucose, gelatin,sucrose, citrate, propyl gallate, and the like. Such compositionstakethe form of solutions, suspensions, tablets, pills, capsules,powders, sustained release formulations and the like.

[0112] Preferably such compositions will takethe form of capsule, capletor tablet and therefore will also contain a diluent such as lactose,sucrose, dicalcium phosphate, and the like; a disintegrant such ascroscarmellose sodium or derivatives thereof; a lubricant such asmagnesium stearate and the like; and a binder such as a starch, gumacacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, andthe like.

[0113] The compounds of the invention, or their pharmaceuticallyacceptable salts, may also be formulated into a suppository using, forexample, about 0.5% to about 50% active ingredient disposed in a carrierthat slowly dissolves within the body, e.g., polyoxyethylene glycols andpolyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

[0114] Liquid pharmaceutically administrable compositions can, forexample, be prepared by dissolving, dispersing, etc., a compound(s) ofthe invention (about 0.5% to about 20%), or a pharmaceuticallyacceptable salt thereof, and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, ethanol and the like, to thereby form a solution orsuspension.

[0115] If desired, a pharmaceutical composition of the invention mayalso contain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

[0116] Actual methods of preparing such dosage forms are known, or willbe apparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state alleviated by the inhibition of factor Xa inaccordance with the teachings of this invention.

[0117] The compounds of the invention, or their pharmaceuticallyacceptable salts, are administered in a therapeutically effective amountwhich will vary depending upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of the compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular disease-states, and the hostundergoing therapy. Generally, a therapeutically effective daily dose isfrom about 0.14 mg to about 14.3 mg/kg of body weight per day of acompound of the invention, or a pharmaceutically acceptable saltthereof; preferably, from about 0.7 mg to about 10 mg/kg of body weightper day; and most preferably, from about 1.4 mg to about 7.2 mg/kg ofbody weight per day. For example, for administration to a 70 kg person,the dosage range would be from about 10 mg to about 1.0 gram per day ofa compound of the invention, or a pharmaceutically acceptable saltthereof, preferably from about 50 mg to about 700 mg per day, and mostpreferably from about 100 mg to about 500 mg per day.

[0118] Preferred Embodiments

[0119] Of the compounds of the invention as set forth above in theSummary of the Invention, several groups of compounds are preferred.

[0120] One preferred group arethose compounds selected from formula (I):

[0121] wherein

[0122] A is —N═;

[0123] Z¹ and Z² are independently —O—, —N(R⁸)— or —OCH₂—;

[0124] R¹ and R³ are independently hydrogen, fluoro, chloro, haloalkyl,—N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸, or—N(R⁸)S(O)₂R¹²;

[0125] R² is hydrogen; halo; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸;—C(O)N(R⁸)R⁹; —N(R⁸)R⁹; —C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3);—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);—N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3);—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

[0126] or R² is aryloxy (optionally substituted by one or more,substituents independently selected from the group consisting of —OR⁸,—C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylal kyl, carboxyalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl));

[0127] or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl);

[0128] or R² is 1-piperazinoyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, carboxy,—C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);

[0129] or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy,—C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, or alkoxycarbonylalkyl);

[0130] or R² is (3,4)-piperidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of alkylcarbonyl,carboxy, —C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, or tetrazolylalkyl);

[0131] or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, —C(O)N(R⁸)R⁹, alkoxycarbonylalkyl oraralklyl);

[0132] or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)N(R⁸)R⁹, or alkoxycarbonylalkyl);

[0133] R⁴ is hydrogen, —OR⁸ or —N(R⁸)R⁹;

[0134] R⁵ is —C(NH)NH₂;

[0135] R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹, —CH(OH)C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3), 1-piperidinoyl, 1-pyrrolidinoyl,(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

[0136] R⁷ is hydrogen, halo, alkyl, —OR⁸, —C(O)N(R⁸)R⁹;

[0137] R⁸ and R⁹ are independently hydrogen, methyl, ethyl or phenyl;and

[0138] R¹² is methyl, ethyl, phenyl or benzyl.

[0139] Of this group of compounds, a preferred subgroup of compounds isthat subgroup wherein

[0140] Z¹ and Z² are independently —O— or —NCH₃—;

[0141] R¹ and R³ are independently hydrogen, fluoro, chloro,trifluoromethyl, amino, —C(O)N(R⁸)R⁹, or —NHC(O)NHR⁹;

[0142] R² is hydrogen; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸; —N(R⁸)R⁹;—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);-N((CH₂)_(n)N(R⁸)R⁹)(CH₂),C(O)OR⁸ (where each n is 1 to 3);—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

[0143] or R² is aryloxy (optionally substituted by one or moresubstituents independently selected from the group consisting of —OR⁸,—C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyal kyl, alkoxycarbonyl al kenyl, carboxyal kenyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, carboxyalkyl, and alkoxycarbonylalkyl);

[0144] or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy andalkoxycarbonyl);

[0145] or R² is (3,4)-piperidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of carboxyalkyl andalkoxycarbonylalkyl);

[0146] or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting ofcarboxyalkyl, alkoxycarbonylalkyl and aralklyl);

[0147] or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of 1-iminoethyl,carboxy, carboxyalkyl, alkoxycarbonyl and alhkoxycarbonylalkyl);

[0148] R⁴ is hydrogen, amino, hydroxy, or methoxy;

[0149] R⁵ is —C(NH)NH₂;

[0150] R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹, —(CH₂)_(m)N(R⁸)R⁹(where m is 0 to 1), (1,2)-imidazolyl substituted by alkyl, or2-imidazolinyl substituted by alkyl;

[0151] R⁷ is hydrogen, methoxy, or hydroxy; and

[0152] R⁸ and R⁹ are independently hydrogen, methyl, ethyl, or phenyl.

[0153] Of this subgroup of compounds, a preferred class of compounds isthat class wherein Z¹ and Z² are both —O—; R¹ and R³ are independentlyhydrogen, fluoro, or chloro; R⁴ is amino, hydrogen, hydroxy or methoxy;R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹, —(CH₂)_(m)N(R⁸)R⁹ (where m is0 or 1), (1,2)-imidazolyl substituted by methyl, or 2-imidazolinyloptionally substituted by methyl; and R⁷ is hydrogen or hydroxy.

[0154] Of this class of compounds, a preferred subclass of compounds isthat subclass wherein R⁴ is hydroxy; R⁶ is dimethylamino ordimethylaminocarbonyl; and R⁷ is hydrogen.

[0155] Of this subclass of compounds, preferred compounds are selectedfrom the following:

[0156]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0157]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonyl-methylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0158]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-propoxy-pyridin-2-yl)oxy]benzamidine;

[0159]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine;

[0160]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0161]4-hydroxy-3-[(3,5-difiuoro-6-(3-dimethylaminocarbonylphenoxy)-4-dimethylamino-pyridin-2-yl)oxy]benzamidine;

[0162]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,2,2-trifluoro-ethoxy)pyridin-2-yl)oxy]benzamidine;

[0163]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;

[0164]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-bromo-3-fluoro-prop-2-oxy)pyridin-2-yl)oxy]benzamidine;

[0165]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;

[0166]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

[0167]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methoxy-pyridin-2-yl)oxy]benzamidine;

[0168]4-hydroxy-3-[(3,5-difluoro-6-13-dimethylaminocarbonylphenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0169]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxymethyl-piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0170]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-1-yl)-pyridin-2-yl)oxy]benzamidine;

[0171]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0172]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(morpholin-4-yl)-pyridin-2-yl)oxy]benzamidine;

[0173]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxymethyl-piperazinyl)pyridin-2-yl)oxy]benzamidine;

[0174]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonyl-methylpiperazinyl)pyridin-2-yl)oxy]benzamidine;

[0175]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0176]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-(morpholin-4-ylmethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0177]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

[0178]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;

[0179]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine;

[0180]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-carboxy-methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0181]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-carboxymethoxypyridin-2-yl)oxy]benzamidine;

[0182]4-hydroxy-3-[(3,5-difiuoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-dimethyl-aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

[0183]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0184]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl]oxy]benzamidine;

[0185]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonyl-methylpyrrolidin-3-yloxy)pyridin-2-yl]oxybenzamidine;

[0186]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0187]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;and

[0188]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)-((carboxymethyl)aminocarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine.

[0189] Of this class of compounds, another preferred subclass ofcompounds is that subclass wherein wherein R⁴ is hydroxy; R⁶ is(1,2)-imidazolyl substituted by methyl or 2-imidazolinyl substituted bymethyl; and R⁷ is hydrogen.

[0190] Of this subclass, preferred compounds are selected from thefollowing:

[0191]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0192]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0193]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

[0194]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)-(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxyenzamidine;

[0195]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(1-(methoxy-carbonyl)ethyl)piperidin-4-yl)aminopyridin-2-yl)oxy]benzamidine;

[0196]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0197]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0198]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0199]4-hydroxy-3-1(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0200]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0201]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0202]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0203]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0204]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0205]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0206]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxybenzamidine;

[0207]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0208]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0209]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0210]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0211]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0212]4-hydroxy-3-1(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0213] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0214]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0215]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0216]4-hydroxy-3-[(3,5-difluoro-4-(3-(1-methylimidazolin-2-yl)phenoxy)-6-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0217]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0218]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0219]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0220]4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(2-methoxy-4-carboxy-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0221]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0222]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0223]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0224]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxyarbonylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0225]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(ethoxycarbonylmethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0226]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0227]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0228]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0229]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0230]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0231]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0232]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0233]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-ethoxy-carbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0234]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0235]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0236] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0237]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-dimethyl-aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

[0238]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0239]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0240]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxy-carbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0241]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(ethoxycarbonyl-methyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0242]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0243]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzyl-piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0244]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)-(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0245]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzyl-piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0246]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;and

[0247]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine.

[0248] Of this class of compound, another preferred subclass ofcompounds is that subclass wherein R⁴ is hydroxy; R⁶ is guanidino; andR⁷ is hydrogen.

[0249] Of this subclass of compounds, preferred compounds are selectedfrom the following:

[0250]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-ethoxycarbonylmethyl)-piperidin-4-yloxy) pyridin-2-yloxy]benzamidine;

[0251]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0252] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4—,(5-ethoxycarbonylpyrrolidin-3-yl-oxy)pyridin-2-yl)oxy]benzamidine;

[0253]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-methoxy-carbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0254]4-hydroxy-3-[(3,5-difluoro-6-(3-guanidino)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0255]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[0256]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0257]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)-pyridin-2-yl)oxy]benzamidine;

[0258]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(methyl)(phenyl)amino-carbonylpyridin-2-yl)oxy]benzamidine;and

[0259]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxy-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine.

[0260] Another preferred group of compounds are selected from formula(VII):

[0261] wherein

[0262] Z¹ and Z² are independently —O—, —N(R⁸)— or —OCH₂—;

[0263] R¹ and R³ are independently hydrogen, fluoro, chloro, haloalkyl,—N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸, or—N(R⁸)S(O)₂R¹²;

[0264] R² is hydrogen; halo; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸;—C(O)N(R⁸)R⁹; —N(R⁸)R⁹; —C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3);—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);—N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3);—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

[0265] or R² is aryloxy (optionally substituted by one or moresubstituents independently selected from the group consisting of —OR⁸,—C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl));

[0266] or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl);

[0267] or R² is 1-piperazinoyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, carboxy,—C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);

[0268] or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy,—C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, or alkoxycarbonylalkyl);

[0269] or R² is (3,4)-piperidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of alkylcarbonyl,carboxy, —C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, or tetrazolylalkyl);

[0270] or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, —C(O)N(R⁸)R⁹, alkoxycarbonylalkyl oraralklyl);

[0271] or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R⁸)R⁹,alkoxycarbonyl or alkoxycarbonylalkyl);

[0272] R⁴ is hydrogen, —OR⁸ or —N(R⁸)R⁹;

[0273] R⁵ is —C(NH)NH₂;

[0274] R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹, —CH(OH)C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3), 1-piperidinoyl, 1-pyrrolidinoyl,(1 ,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

[0275] R⁷ is hydrogen, halo, alkyl, —OR⁸, —C(O)N(R⁸)R⁹;

[0276] R⁸ and R⁹ are independently hydrogen, methyl, ethyl or phenyl;

[0277] R¹² is methyl, ethyl, phenyl or benzyl.

[0278] Of this group of compounds, a preferred subgroup of compounds isthat subgroup wherein Z¹ and Z² are independently —O— or —NCH₃—;

[0279] R¹ and R³ are independently hydrogen, fluoro, chloro,trifluoromethyl, amino, —C(O)N(R⁸)R⁹, or —NHC(O)NHR⁹;

[0280] R² is hydrogen; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸; —N(R⁸)R⁹;—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);-N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3);—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

[0281] or R² is aryloxy (optionally substituted by one or moresubstituents independently selected from the group consisting of —OR⁸,—C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl,carboxyalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, tetrazolyl,morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted byalkyl));

[0282] or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxyalkyl, and alkoxycarbonylalkyl);

[0283] or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy andalkoxycarbonyl);

[0284] or R² is (3,4)-piperidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of carboxyalkyl andalkoxycarbonylalkyl);

[0285] or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting ofcarboxyalkyl, alkoxycarbonylalkyl and aralklyl);

[0286] or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of 1-iminoethyl,carboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl);

[0287] R⁴ is hydrogen, amino, hydroxy, or methoxy;

[0288] R⁵ is —C(NH)NH₂;

[0289] R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹, —(CH₂)_(m)N(R⁸)R⁹(where m is 0 to 1), (1,2)-imidazolyl substituted by alkyl, or2-imidazolinyl substituted by alkyl;

[0290] R⁷ is hydrogen, methoxy, or hydroxy; and

[0291] R⁸ and R⁹ are independently hydrogen, methyl, ethyl, or phenyl.

[0292] Of this subgroup of compounds, a preferred class of compounds isthat class wherein Z¹ and Z² are both —O—; R¹ and R³ are independentlyhydrogen, fluoro, or chloro; R⁴ is amino, hydrogen, hydroxy or methoxy;R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹, —(CH₂)_(m)N(R⁸)R⁹ (where m is0 or 1), (1,2)-imidazolyl substituted by methyl, or 2-imidazolinyloptionally substituted by methyl; and R⁷ is hydrogen or hydroxy.

[0293] Of this class of compounds, a preferred subclass of compounds isthat subclass wherein R⁴ is hydroxy; R⁶ is dimethylamino ordimethylaminocarbonyl; and R⁷ is hydrogen.

[0294] Of this subclass of compounds, preferred compounds are4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-methoxypyridin-4-yl)-oxy]benzamidine;and

[0295]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonyl-phenoxy)-2-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-4-yl)oxy]benzamidine.

[0296] Preparation of Compounds of The Invention

[0297] As a matter of convenience, the following description of thepreparation of the compounds of the invention is directed to thepreparation of compounds of formula (I). It is understood, however, thatsimilar synthetic processes may be used to preparethe compounds offormula (II), (III), (IV), (V), (VI), (VII) and (VIII). It is alsounderstood that in the following description, combinations ofsubstituents and/or variables (e.g., R⁴ and R⁵) on the depicted formulaeare permissible only if such combinations result in stable compounds.

[0298] A. Preparation of Intermediates

[0299] 1. Compounds of formula (C)

[0300] Compounds of formula (C), as shown below, are intermediates inthe preparation of the compounds of the invention. As illustrated belowin Reaction Scheme 1, compounds of formula (C) are prepared fromcompounds of formulae (A) and (B) wherein X is chloro or fluoro andR^(2a) is —N(R⁸)R⁹, —N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3) orpiperazinyl (optionally substituted by alkyl, carboxy, carboxyalkyl,alkoxycarbonyl or alkoxycarbonylalkyl); and each R⁸ and R⁹ isindependently hydrogen, alkyl, aryl or aralkyl:

[0301] Compounds of formula (A) and (B) can be prepared according tomethods known to those of ordinary skill in the art or are commerciallyavailable, for example, from Aldrich Chemical Company, Inc. or fromMaybridge Co.

[0302] In general, compounds of formula (C) are prepared by reacting acompound of formula (A) with an equimolar amount of a compound offormula (B) at 0° C. to 40° C., preferably at ambient temperature, inthe presence of a base, e.g., triethylamine, or in the presence of asecond equivalent of the compounds of formula (B). The compounds offormula (C) are isolated from the resulting reaction mixture byconventional methods.

[0303] 2. Compounds of formula (F)

[0304] Compounds of formula (F), as shown below, are also intermediatesin the preparation of the compounds of the invention. As illustratedbelow in Reaction Scheme 2, compounds of formula (F) are prepared fromcompounds of formulae (D) and (E) where each X is independently chloroor fluoro; and R² is alkoxy, haloalkoxy, —O(CH)_(p)C(O)OR⁸ (where p is 1to 6), —N(R⁸)R⁹, —N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3),—N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n is independently1 to 3), morpholin-4-yl, 3-tetrahydrofuranyloxy; or R² is aryloxy(optionally substituted by one or more substituents independentlyselected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹, halo, alkyl,alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is 1-piperidinyl (optionally substitutedby alkoxycarbonyl or alkoxycarbonylalkyl); or R² is 1-piperazinyl(optionally substituted by alkyl, alkoxycarbonyl oralkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl ortetrazolylalkyl); or R² is piperidin-4-ylamino (wherein the amino isoptionally substituted by alkyl and the piperidinyl group is optionallysubstituted by alkyl, alkoxycarbonyl, alkoxycarbonylalkyl or aralklyl);or R² is 3-pyrrolidinyloxy (optionally substituted by alkyl, aralkyl oralkoxycarbonylalkyl); and each R⁸ and R⁹ is independently hydrogen,alkyl, aryl or aralkyl:

[0305] Compounds of formulae (D) and (E) are commercially available, forexample, from Aldrich Chemical Company, Inc., or may be preparedaccording to methods known to those skilled in the art.

[0306] In general, compounds of formula (F) are prepared by treating acompound of formula (D) with a compound of formula (E) in an aproticsolvent, for example, methylene chloride, at between about 0° C. and 50°C., preferably at ambient temperature, and, if the hydrogen in thecompound of formula (E) is an hydroxyl hydrogen, in the presence of abase, for example, cesium carbonate. The compound of formula (F) isisolated from the reaction mixture by standard techniques.

[0307] 3. Compounds of formulae (J) and (K)

[0308] Compounds of formulae (J) and (K), as shown below, are alsointermediates in the preparation of the compounds of the invention. Asillustrated below in Reaction Scheme 3, compounds of formula (J) and (K)are prepared from compounds of formula (G) and formula (H) where A is—N═ or —C(R¹¹)═ (where R¹¹ is hydrogen, alkyl or halo); X is fluoro ofchloro; R¹ and R³ are independently hydrogen, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, nitro, —N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹,—C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸,—N(R⁸)S(O)₂R¹², or —N(R⁸)C(O)N(R⁸)CH₂—C(O)N(R⁸)R⁹; R² is hydrogen,alkyl, haloalkoxy, —OR¹², —C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹,—C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3), —N(R⁸)(CH₂)_(n)C(O)OR⁸(where n is 1 to 3), —N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each nis 1 to 3), —O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3),—O(CH₂)_(p)C(O)OR⁸ (where p is 1 to 6),—N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n is independently1 to 3), morpholin-4-yl, 3-tetrahydrofuranoxy; or R² is aryloxy(optionally substituted by one or more substituents independentlyselected from the group consisting of —OR¹², —C(O)N(R⁸)R⁹, halo, alkyl,alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, aminocarbonylakenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is1-piperazinoyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkoxycarbonyl, andalkoxycarbonylalkyl); or R² is piperidin-1-yl (optionally substituted byone or more substituents selected from the group consisting ofalkoxycarbonyl, and alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,and tetrazolylalkyl); or R² is piperidin-4-ylamino (wherein the amino isoptionally substituted by alkyl and the piperidinyl group is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkoxycarbonyl, alkoxycarbonylalkyl and aralklyl);or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,alkoxycarbonyl and alkoxycarbonylalkyl); R⁴ is independently hydrogen,halo, alkyl, nitro, —OR¹², —C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹, or—N(H)C(O)R⁸; each R⁸ and R⁹ is independently hydrogen, alkyl, aryl oraralkyl; and R¹² is alkyl, aryl or aralkyl:

[0309] Compounds of formula (G) include compounds of formulae (C) and(F) as described above, or may be prepared by methods described hereinorby methods known to one of ordinary skill in the art. They may also becommercially available, for example, from Aldrich Chemical Co., Inc. orfrom Maybridge Co. Compounds of formula (H) may be prepared by methodsknown to one of ordinary skill in the art or may be commerciallyavailable, for example, from Aldrich Chemical Co., Inc.

[0310] In general, the compounds of formulae (J) and (K) are prepared byreacting a compound of formula (G) with a compound of formula (H) (in anequimolar amount for a compound of formula (K) and with two or moreequivalents of a compound of formula (H) for a compound of formula (J))in the presence of a base, e.g., sodium hydride or cesium carbonate, attemperatures between about 20° C. and 120° C., preferably, for compoundsof formula (J), at temperatures of around 50° C., in an aprotic solvent,for example, dimethylformamide, DMSO or acetonitrile, for a period oftime sufficient to completethe desired reaction as monitored by thinlayer chromatography (TLC). Compounds of formulae (J) and (K) arethenisolated from the reaction mixture by standard isolation techniques.

[0311] In a similar manner, compounds of formula (G) may be treated withcompounds of formula (H) wherein the hydroxy group is replaced by anamino group to produce compounds of formulae (J) and (K) wherein theether connecting group is replaced by an amino connecting group. Theamino group can then be alkylated by standard procedures.

[0312] Compounds of formulae (J) and (K) wherein R⁴ is an amino groupmay be further treated with an alkylsulfonyl halide, e.g.,methylsulfonylchloride, under basic conditions at ambient temperature toproduce compounds of formulae (J) and (K) wherein R⁴ is —N(H)S(O)₂R¹².

[0313] 4. Compounds of formula (M)

[0314] Compounds of formula (M), as shown below, are also intermediatesin the preparation of the compounds of the invention. As illustratedbelow in Reaction Scheme 4, compounds of formula (M) are prepared fromcompounds of formula (K) and formula (L) where A is —N═ or —C(R¹¹)═(where R¹¹ is hydrogen, alkyl or halo); X is fluoro of chloro; R¹ and R³are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,nitro, —N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹, —C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, or—N(R⁸)C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹; R² is hydrogen, alkyl, haloalkoxy, —OR¹²,—C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹, —C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is0 to 3), —N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3),—N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3),—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3), —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6), —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3), morpholin-4-yl, 3-tetrahydrofuranoxy; or R² isaryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of —OR¹², —C(O)N(R⁸)R⁹,halo, alkyl, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl,alkoxycarbonylalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl)); or R² ispiperazin-1-yl (optionally substituted by one or more substituentsindependently selected from the group consisting of alkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is 1-piperazinoyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); orR² is piperidin-1-yl (optionally substituted by one or more substituentsselected from the group consisting of alkoxycarbonyl, andalkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, andtetrazolylalkyl); or R² is piperidin-4-ylamino (wherein the amino isoptionally substituted by alkyl and the piperidinyl group is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkoxycarbonyl, alkoxycarbonylalkyl and aralklyl);or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,alkoxycarbonyl and alkoxycarbonylalkyl); R⁴ and R⁷ are independentlyhydrogen, halo, alkyl, nitro, —OR¹², —C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹,or —N(H)C(O)R⁸; R⁶ is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino,ureido, guanidino, —OR¹², —C(NH)NH₂, —C(NH)NHOH, —C(O)R¹⁰,—(CH₂)_(m)C(O)N(R⁸)R⁹ (where m is 0 to 3), —CH(OH)C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3), —(CH₂)_(m)C(O)OR⁵ (where m is 0to 3), —N(H)C(O)R⁸, (1,2)-tetrahydropyrimidinyl (optionally substitutedby alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ isindependently hydrogen, alkyl, aryl, or aralkyl; and R¹² is alkyl, arylor aralkyl:

[0315] Compounds of formula (K) are prepared according to the methodsdescribed herein (see Reaction Scheme 3 above). Compounds of formula (L)are commercially available, for example, from Aldrich Chemical Co., orfrom Maybridge Co., or may be prepared according to methods known tothose of ordinary skill in the art.

[0316] In general, the compounds of formula (M) are prepared in a mannersimilar to that described above for compounds of formula (J) and (K).

[0317] Compounds of formula (M) where R⁴ or R⁷ is hydroxy may be reactedwith a haloalkane, such as iodomethane, under standard conditions toproducethe corresponding compounds of formula (M) where R⁴ or R⁷ isalkoxy.

[0318] Compounds of formula (M) where R⁶ or R⁷ contains —C(O)OR⁸ whereR⁸ is alkyl or aryl may be hydrolyzed under basic conditions (forexample, in the presence of sodium hydroxide) to produce compounds offormula (M) where R⁶ or R⁷ contains —C(O)OR⁸ where R⁸ is hydrogen.

[0319] Compounds of formula (M) wherethe ether connecting group has beenreplaced by an unsubstituted amino connecting group may be treated withan alkylating agent, such as iodomethane, in the presence of a base, toproduce compounds of formula (M) wherein the amino connecting group issubstituted by alkyl, aryl, or aralkyl. In addition, compounds offormula (K) can be treated with a compound of formula (L) wherein thehydroxy group is replaced by a hydroxymethyl (—CH₂OH) group toproducethe corresponding compounds of formula (M).

[0320] Compounds of formula (M) where each R⁶ and R⁷ independentlycontains —C(O)OR⁸ where R⁸ is hydrogen may be amidated or esterifiedunder standard conditions to produce compounds of formula (M) where R⁶or R⁷ contains —C(O)OR⁸ where R⁸ is alkyl, aryl or aralkyl, or compoundsof formula (M) where R⁶ or R⁷ contains —C(O)N(R⁸)R⁹ where R⁸ and R⁹ areindependently hydrogen, alkyl, aryl or aralkyl.

[0321] Compounds of formula (M) where R³ is nitro may be reduced understandard conditions to produce compounds of formula (M) where R³ isamino; which can then be reacted with the appropriate acid halide oraryl-or alkylsulfonyl halide to produce compounds of formula (M) whereR³ is —N(R⁸)C(O)R⁸ or —N(R⁸)S(O)₂R¹² where R⁸ and R¹² are as definedabove. In addition, compounds of formula (M) where R³ is amino can bereacted with an isocyanate or chloroformate to produce compounds offormula (M) where R³ is —N(R⁸)C(O)N(R⁸)R⁹ or —N(R⁸)C(O)OR⁸.

[0322] 5. Compounds of formula (P)

[0323] Compounds of formula (P), as shown below, are also intermediatesin the preparation of the compounds of the invention, particularly thosecompounds of formula (I) wherein A is —C(R¹¹)═. As illustrated below inReaction Scheme 5, compounds of formula (P) are prepared from compoundsof formulae (N) and (O) where X is fluoro or chloro; R¹ and R³ areindependently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,—N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹, —C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹,—N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸, —N(R⁸)S(O)₂R¹² ₁ or—N(R⁸)C(O)N(R⁸)CH₂—C(O)N(R⁸)R⁹; R² is hydrogen, alkyl, haloalkoxy, —OR¹²—C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹, —C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is0 to 3), —N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3),-N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3),—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3), —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6), —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3), morpholin-4-yl, 3-tetrahydrofuranoxy; or R² isaryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of —OR¹², —C(O)N(R⁸)R⁹,halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholi n-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl); or R² is 1-piperazinoyl (optionally substituted byone or more substituents selected from the group consisting of alkyl,carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R²is piperidin-1-yl (optionally substituted by one or more substituentsselected from the group consisting of carboxy, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of alkylcarbonyl, carboxy, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl and aralklyl); or R²is 3-pyrrolidinyloxy (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aralkyl, amidino,1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl andalkoxycarbonylalkyl); each R⁸ and R⁹ is independently hydrogen, alkyl,aryl, or aralkyl; R¹¹ is hydrogen, alkyl or halo; and R¹² is alkyl, arylor aralkyl:

[0324] Compounds of formulae (N) and (O) may be prepared according toordinary skill in the art, or by methods described herein, or may becommercially available, for example, from Aldrich Chemical Co., Inc.

[0325] In general, compounds of formula (P) are prepared in the samemanner as described above for compounds of formula (J), except thetemperatures at which the reaction is run are elevated to between about50° C. and 130° C. The compounds of formula (P) are isolated from thereaction mixture by conventional techniques.

[0326] B. Preparation of the Compounds of the Invention

[0327] In the following Reaction Scheme 6, compounds of formula (Ia) arecompounds of formula (I) as described above in the Summary of theInvention wherein Z¹ and Z² are —O—. As illustrated below in ReactionScheme 6, wherein A is —N═ or —C(R¹¹)═ (where R¹¹ is hydrogen, alkyl orhalo); R¹ and R³ is hydrogen, halo, alkyl, haloalkyl, alkoxy,haloalkoxy, nitro, —N(R⁸)R⁹, —C(O)OR¹³, —C(O)N(R⁸)R⁹,—C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸,—N(R⁸)S(O)₂R¹², or —N(R⁸)C(O)N(R⁸)CH₂—C(O)N(R⁸)R⁹; R² is hydrogen,alkyl, haloalkoxy, —OR⁸, —C(O)OR¹³,—C(O)N(R⁸)R⁹, —N(R⁸)R⁹,—C(O)N(R⁸)(CH₂)_(m)C(O)OR¹³ (where m is 0 to 3), —N(R⁸)(CH₂)_(n)C(O)OR1³(where n is 1 to 3), —N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR¹³ (where each nis 1 to 3), —O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3),—O(CH₂)_(p)C(O)OR¹³ (where p is 1 to 6),—N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR¹³ (where each n is independently1 to 3), morpholin-4-yl, 3-tetrahydrofuranoxy; or R² is aryloxy(optionally substituted by one or more substituents independentlyselected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹, halo, alkyl,carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl); or R² is 1-piperazinoyl (optionally substituted byone or more substituents selected from the group consisting of alkyl,carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R²is piperidin-1-yl (optionally substituted by one or more substituentsselected from the group consisting of carboxy, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of alkylcarbonyl, carboxy, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl and aralklyl); or R²is 3-pyrrolidinyloxy (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aralkyl, amidino,1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl andalkoxycarbonylalkyl); R⁴ and R⁷ are independently hydrogen, halo, alkyl,nitro, —OR⁸, —C(O)OR¹³, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹, or —N(H)C(O)R⁸; R⁶ ishalo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino,—OR⁸, —C(NH)NH₂, —C(NH)NHOH, —C(O)R¹⁰, —(CH₂)_(m)C(O)N(R⁸)R⁹ (where m is0 to 3), —CH(OH)C(O)N(R⁸)R⁹, —(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3),—(CH₂)_(m)C(O)OR¹³ (where m is 0 to 3), —N(H)C(O)R⁸,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ isindependently hydrogen, alkyl, aryl, or aralkyl; R¹⁰ is hydrogen, alkyl,aryl, aralkyl, 1-pyrrolidinyl, 4-morpholinyl, 4-piperazinyl,4-(N-methyl)piperazinyl, or 1-piperidinyl; R¹² is alkyl, aryl oraralkyl; and R¹³ is hydrogen, alkyl or aralkyl; compounds of formula(la) are prepared from compounds of formula (Q) as follows:

[0328] Compounds of formula (Q) are prepared as described herein abovefor compounds of formulae (J), (M), and (P).

[0329] In general, compounds of formula (Ia) are prepared from compoundsof formula (Q) by dissolving the compound of formula (Q) in an anhydrousalkanol, preferably ethanol and then treating the solution with ananhydrous mineral acid, preferably HCl, while maintaining the reactiontemperatures between about −78° C. and ambient temperature for between 2hours and 24 hours, allowing the temperature to rise to ambienttemperature while monitoring for reaction completion, for example,through thin layer chromatography. The solvent is then removed and theresulting residue dissolved in fresh anhydrous alkanol, preferablyethanol. The resulting solution was then treated with anhydrous ammoniaat ambient pressure or in a sealed flask, at temperatures from betweenambient temperature and 100° C. for about 1 to about 5 hours. Thecompounds of formula (Ia) arethen isolated from the reaction mixture bystandard techniques.

[0330] Compounds of formula (Ia) wherein R⁶ is —C(NH)NH₂ or —C(NH)NHOHare produced from the corresponding cyano compounds.

[0331] Alternatively, instead of treating the resulting residue abovewith anhydrous ammonia, the resulting residue may be treated with acompound of the formula NH₂OR⁸ to afford the corresponding compound offormula (Ia) wherein R⁵ is —C(NH)N(H)OR⁸.

[0332] In addition, compounds of formula (Ia) which contain a —C(O)OR¹³group may be treated under standard transesterification conditions withan phenol or a naphthol (either optionally substituted by halo, alkyl,alkoxy, amino, nitro or carboxy) to produce compounds of the inventionwhich contain a —C(O)OR⁸ group where R⁸ is aryl.

[0333] Compounds of formula (Ia) wherein R⁶ is —C(NH)NH₂ or—C(NH)N(H)OR¹³ are produced from the corresponding cyano compounds in asimilar manner as that described above for the compounds of formula(Ia).

[0334] In addition, compounds of formula (Ia) where R¹, R², R³, R⁴, andR⁷ contains a —N(R⁸)R⁹ group where R⁸ and R⁹ are hydrogen, can betreated with the appropriate alkylating agents to afford thecorresponding compounds of formula (Ia) where R¹, R², R³, R⁴, and R⁷contains —N(R⁸)R⁹, —N(R⁸)SO)₂R¹², —N(R⁸)C(O)N(R⁸)R⁹,—N(R⁸)C(O)N(R⁸)CH₂—C(O)N(R⁸)R⁹, or —N(R⁸)C(O)R⁸ where each R⁸ and R⁹ isindependently hydrogen, alkyl, aryl or aralkyl, and R¹² is alkyl, arylor aralkyl.

[0335] Compounds of formula (Ia) may be further treated with theappropriate acid halide, preferably acid chloride, or with theappropriate acid anhydride or an equivalent, to yield compounds of theinvention wherein R⁵ is —C(NH)N(H)C(O)R⁸ where R⁸ is hydrogen, alkyl,aryl or aralkyl.

[0336] Alternatively, compounds of formula (Ia) may further be treatedwith carbamoyl chlorides or their equivalents to yield compounds of theinvention where R⁵ is —C(NH)N(H)C(O)OR¹² where R¹² is alkyl, aryl oraralkyl.

[0337] Alternatively, compounds of formula (Ia) may be further treatedwith compounds of the formula R¹²—S(O)₂-imidazole where R¹⁶ is describedin the Summary of the Invention in a polar solvent, such as methylenechoride, at ambient temperature to afford compounds of the inventionwhere R⁵ is —C(NH)N(H)S(O)₂R¹².

[0338] Alternatively, compounds of formula (Ia) may be further treatedwith an appropriatly N—R⁹-substituted phenylcarbamate in a polarsolvent, preferably methylene chloride, at ambient temperature, forabout 6 to 24 hours, preferably for about 12 hours, to afford compoundsof the invention where R⁵ is —C(NH)N(H)C(O)N(R⁸)R⁹.

[0339] Compounds of formula (Ia) wherein R¹, R² or R³ contains—C(O)N(R⁸)R⁹ or —C(O)OR¹ ³ where each R⁸ and R⁹ are independently alkyl,haloalkyl, aryl or aralkyl, and R¹³ is alkyl or aralkyl may behydrolyzed under acidic conditions to prepare compounds of formula (Ia)where R¹, R² or R³ contains —C(O)OR⁸ where R⁸ is hydrogen.

[0340] Under the same conditions as previously described, compounds offormula (Ia) where R¹, R² or R³ contains —C(O)OR¹³ where R¹³ ishydrogen, alkyl, or aralkyl, may be amidated to form compounds offormula (Ia) where R¹, R² or R³ contains —C(O)N(R⁸)R⁹ where R⁸ and R⁹are independently hydrogen, alkyl, aryl or aralkyl.

[0341] Compounds of formula (Ia) where R⁴ is —OR⁸ where R⁸ is alkyl,aryl or aralkyl, may be converted to compounds of formula (Ia) where R⁴is —OR⁸ where R⁸ is hydrogen by treatment with boron tribromide in anaprotic solvent, for example, methylene chloride, at temperatures atfirst between −80° C. and 0° C., then at ambient temperature, for about4 hours to about 16 hours.

[0342] Alternatively, compounds of formula (Ia) where R⁴ is —OR⁸ whereR⁸ is arylmethyl, preferably, benzyl, may be treated with hydrogen andthe appropriate catalyst, for example, palladium on carbon, to givecompounds of formula (Ia) where R⁴ is —OR⁸ where R⁸ is hydrogen.

[0343] Compounds of formula (Ia) where R² is 3-pyrrolidinyloxysubstituted by arylmethyl on the nitrogen may be treated under standardhydrogenolysis conditions to removethe arylmethyl group to producecompounds of formula (Ia) where R² is unsubstituted 3-pyrrolidinyloxy,which can then be reacted with the appropriate imidate to produce thecompounds of formula (Ia) where R² is 3-pyrrolidinyloxy substituted by1-iminoethyl, or with the appropriate haloalkyl esters to produce thecompounds of formula (Ia) where R² is 3-pyrrolidinyloxy substituted byalkoxycarbonylalkyl.

[0344] In summary, compounds of the invention, are prepared by:

[0345] 1) reacting a compound of formula (A) as described above with acompound of formula (B) as described above under the conditions asdescribed above to produce a compound of formula (C) as described above,which is an intermediate in the preparation of the compounds of theinvention; or

[0346] 2) reacting a compound of formula (D) as described above with acompound of formula (E) as described above under conditions as describedabove to produce a compound of formula (F) as described above, which isan intermediate in the preparation of the compounds of the invention; or

[0347] 3) reacting a compound of formula (G) as described above, whichcan be a compound of formula (C) as described above or a compound offormula (F) as described above, with a compound of formula (H) asdescribed above under conditions as described above to produce acompound of formula (J) or a compound of formula (K) as described above,which are intermediates in the preparation of the compounds of theinvention; then

[0348] 4) reacting a compound of formula (K) as described above with acompound of formula (L) as described above under conditions as describedabove to produce a compound of formula (M) as described above, which isan intermediate in the preparation of the compounds of the invention; or

[0349] 5) reacting a compound of formula (N) as described above with acompound of formula (O) as described above under conditions as describedabove to produce a compound of formula (P) as described above, which isan intermediate in the preparation of the compounds of the invention:then

[0350] 6) reacting a compound of formula (Q) as described above, whichcan be a compound of formula (J), a compound of formula (M) or acompound of formula (P) as described above, with the appropriate reagentunder the conditions as described above to form compounds of formula(Ia) as described above.

[0351] Similar reactions may be performed on similar starting materialsand intermediates to produce the corresponding compounds of theinventions not depicted in the Reaction Schemes above.

[0352] In addition, all compounds of the invention that exist in freebase form or free acid form may be converted to their pharmaceuticallyacceptable salts by treatment with the appropriate inorganic or organicacid, or by the appropriate inorganic or organic base. Salts of thecompounds of the invention can also be converted to the free base formor to the free acid form or to another salt.

[0353] The following specific preparations and examples are provided asa guide to assist in the practice of the invention, and are not intendedas a limitation on the scope of the invention.

PREPARATION 1 4-Methoxy-2,3,5,6-tetrafluoropyridine

[0354] A. To pentafluoropyridine (1.0 g, 5.9 mmol) in petroleum ether(60 mL) at 0° C. was added sodium methoxide (0.32 mg, 5.9 mmol). Afterstirring for 12 hours at ambient temperature, the reaction was washedwith water, dried (MgSO₄), and the solvent was removed in vacuo to give4-methoxy-2,3,5,6-tetrafluoropyridine; NMR (CDCl₃) 4.3 ppm.

[0355] B. In a similar manner, the following compounds were made:

[0356] 2,3,5,6-tetrafluoro-4-(2,2,2-trifluoroethoxy)pyridine; and

[0357] 2,3,5,6-tetrafluoro-4-(1,3-difluoroprop-2-oxy)pyridine.

PREPARATION 2 4-Dimethylamino-2,3,5,6-tetrafluoropyridine

[0358] A. To methylene chloride (50 mL) cooled in an ice bath was addedpentafluoropyridine (2.0 g, 11.8 mmol) and dimethylamine (2.97 mL of a40% solution in water, 24 mmol). After stirring for 30 minutes thesolution was washed with water, and dried over basic alumina. Thesolvent was removed in vacuo to give4-dimethylamino-2,3,5,6-tetrafluoropyridine; NMR (CDCl₃) 3.13 (m,6) ppm.

[0359] B. In a similar manner, the following compounds were made:

[0360] 1-(2,3,5,6-tetrafluoropyridin-4-yl)piperidine-4-carboxylic acid,ethyl ester; NMR (CDCl₃) 4.15 (q,2), 3.7 (m,2), 3.25 (m,2), 2.55 (m,1),2.05 (m,2), 1.9 (m,2), 1.15 (t,3) ppm;

[0361] 1-(2,3,5,6-tetrafluoropyridin-4-yl)piperidine-3-carboxylic acid,ethyl ester; NMR (CDCl₃) 4.15 (q,2), 3.8 (m,1), 3.55 (m,1), 3.4 (m,1),3.25 (m,1), 2.7 (m,1), 2.15 (m,1), 1.8 (m,3), 1.15 (t,3) ppm;

[0362] 4-(piperidin-1-yl)-2,3,5,6-tetrafluoropyridine; NMR (CDCl₃) 3.4(m,4), 1.7 (m,6) ppm;

[0363] 4-(4-methylpiperazin-1-yl)-2,3,5,6-tetrafluoropyridine; NMR(CDCl₃) 3.45 (m,4), 2.5 (m,4), 2.3 (s,3) ppm;

[0364] 4-(2,3,5,6-tetrafluoropyridin-4-yl)piperazine-1-acetic acid,ethyl ester; NMR (CDCl₃) 4.2 (q,2), 3.55 (m,4), 3.3 (s,2), 2.7 (m,4),1.3 (t,3) ppm;

[0365] N-methyl-N-(2,3,5,6-tetrafluoropyridin-4-yl)glycine, ethyl ester;and

[0366] 4-(morpholin-1-yl)-2,3,5,6-tetrafluoropyridine.

PREPARATION 3 1-[(2,6-Dichloropyridin-4-yl)carbonyl]-4-methylpiperazine,Hydrochloride

[0367] To methylene chloride (15 mL) was added2,6-dichloropyridine-4-carbonyl chloride (1.0 g, 4.8 mmol) and1-methylpiperazine (0.48 g, 4.8 mmol). After stirring for 1 day, thereaction was poured into ether. The resulting solid was filtered to give1-[(2,6-dichloropyridin-4-yl)-carbonyl]-4-methylpiperazine,hydrochloride.

PREPARATION 4 3-(1-Methylimidazolin-2-yl)phenol, Hydrobromide

[0368] A. To ethanol (200 mL) was added 3-methoxybenzonitrile (10.9 g,82 mmol). The solution was cooled in an ice bath and HCl (g) was bubbledinto the solution. The reaction was warmed to ambient temperature andstirred for 2 days. The solvent was removed in vacuo and the residue wasslurried in ethanol (20 mL). N-methylethylene--diamine (12 g, 1 60 mmol)was added and the reaction was refluxed for 7 hours. The solvent wasremoved in vacuo and the residue was chromatographed on silica gel withmethylene chloride/methanol/ammonium hydroxide (20/1/0.1). The resultingoil was dissolved in 48% HBr (20 mL) and refluxed for 19 hours. Themixture was cooled to ambient temperature and the solvent was removed invacuo to give 3-(1-methyl-imidazolin-2-yl)phenol, hydrobromide.

[0369] B. In a similar manner, the following compound is made:

[0370] 3-(1-methyltetrahydropyrimidin-2-yl)phenol, hydrobromide.

PREPARATION 5 3,3′-[2,6-Pyridinediylbis(oxy)]bis(benzonitrile)

[0371] A. To sodium hydride (0.38 g, 9.5 mmol) in N,N-dimethylformamide(3 mL) was added 3-cyanophenol (1.1 g, 8.9 mmol) and2,6-difluoropyridine (o.4 mL, 4.4 mmol). After heating in an oil bath at100° C. for 15 hours the reaction was partitioned with ethyl acetate andwater. The organic layer was separated, washed with water, dried(Na₂SO₄), and the solvent was removed in vacuo. The residue waschromatographed on silica gel (50 g) with methylene chloride/hexane(3/1) to give 3,3′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile).Recrystallization from ethyl acetate/hexane gave pure3,3′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃) 7.79(t,1), 7.45 (m,4), 7.32 (m,4), 6.72 (d,2) ppm.

[0372] B. In a similar manner, the following compounds were made:

[0373] 4,4′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃) 7.8(t,1), 7.6 (d,4), 7.2 (d,4), 6.8 (d,2) ppm;

[0374] 3,3′-[3,5-dichloro-2,6-pyridinediylbis(oxy)]bis(benzonitrile);NMR (CDCl₃) 7.9 (s,1), 7.45 (m,4), 7.2 (m,4) ppm;

[0375] 4,4′-[3,5-dichloro-2,6-pyridinediylbis(oxy)]bis(benzonitrile);NMR (CDCl₃) 7.95 (s,1), 7.6 (d,4), 7.1 (d,4) ppm;

[0376] 2,6-bis(3-cyanophenoxy)pyridine-4-carboxylic acid, ethyl ester;NMR (CDCl₃) 7.45 (m,4), 7.35 (m,6), 4.45 (q,2), 1.45 (t,3) ppm;

[0377] 2,6-bis(3-cyanophenoxy)pyridine-3-carboxylic acid, ethyl ester;NMR (CDCl₃) 8.4 (d,1), 7.45 (m,4), 7.25 (m,4), 6.75 (d,1), 4.4 (q,2),1.45 (t,3) ppm;

[0378] 3,3 ′-[3,5-difluoro-2,6-pyridinediylbis(oxy)Ibis(benzonitrile);NMR (CDCl₃) 7.55 (t,1), 7.45 (m,4), 7.29 (m,4) ppm;

[0379] 3,3′-[2,6-pyrazinediylbis(oxy)bis(benzonitrile); NMR (CDCl₃) 8.2(s,2), 7.5 (m,4), 7.3 (m,4) ppm;

[0380] 3,3′-[2,6-pyrimidinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃)8.4 (d,2), 7.5 (m,4), 7.4 (m,4), 6.8 (d,1) ppm;

[0381]3,3′-[3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy);bis(benzonitrile);NMR (CDCl₃) 7.44 (m,4), 7.27 (m,4), 2.4 (s,3) ppm;

[0382] 3,3′-14-nitro-1,3-phenylenebis(oxy)]bis(benzonitrile); NMR(CDCl₃) 8.13 (d,1), 7.5 (m,4), 7.3 (m,4), 6.84 (dd,1), 6.69 (d,1) ppm;and

[0383]3,3′-[3-trifluoromethyl-2,6-pyridinediylbis(oxy)jbis(benzonitrile); NMR(CDCl₃) 8.05 (t,1), 7.5 (m,4), 7.3 (m,4), 6.8 (d,₁) ppm.

PREPARATION 6 3-[(3,5,6-Trifluoro-4-methylpyridin-2-yl)oxy]benzonitrile

[0384] A. To 2,3,5,6-tetrafluoro-4-methylpyridine (0.71 g, 4.3 mmol)dissolved in acetonitrile (5 mL) was added 3-cyanophenol (0.5 g, 4.2mmol) and cesium carbonate (1.44 g, 4.4 mmol). The reaction was heatedin an oil bath at 45° C. for 16 hours and partitioned with ether andwater. The organic layer was separated, washed with brine, dried(Na₂SO₄), and the solvent removed in vacuo. Chromatography on silica gelwith methylene chloride/hexane (7/3) gave3-[(3,5,6-trifluoro-4-methylpyridin-2-yl)-oxy]benzonitrile; NMR (CDCl₃)7.55 (m,2), 7.45 (m,2), 2.24 (s,3) ppm.

[0385] B. In a similar manner, the following compounds were made:

[0386] 4-[(2,3,5,6-tetrafluoropyridin-4-yl) oxy]-3-methoxybenzoic acid,ethyl ester;

[0387]3-(4-dimethylamino-3,5,6-trifluoropyridin-2-yl)-4-methoxybenzonitrile;NMR (CDCl₃) 7.55 (d,1), 7.4 (s,1), 7.05 (d,3), 3.85 (s,3), 3.15 (s,6)ppm;

[0388]1-[(2-(5-cyano-2-methoxyphenoxy)-3,5,6-trifluoropyridin-4-yl)piperidine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.5 (d,1), 7.4 (s,1), 7.05 (d,1), 4.15(q,2), 3.8 (s,3), 3.7 (m,2), 3.25 (m,2), 2.55 (m,1), 2.1 (m,2), 1.9(m,2), 1.15 (t,3) ppm;

[0389]1-[(2-(5-cyano-2-methoxyphenoxy)-3,5,6-trifluoropyridin-4-yl)piperidine-3-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.5 (d,1), 7.4 (s,1), 7.05 (d,1), 4.15(q,2), 3.8 (s,3), 3.8 (m,1), 3.55 (m,1), 3.4 (m,1), 3.25 (m,1), 2.7(m,1), 2.15 (m,1), 1.8 (m,3), 1.15 (t,3) ppm;

[0390] 2-chloro-6-(5-cyano-2-methoxyphenoxy)pyridine-4-carboxylic acid,ethyl ester; NMR (CDCl₃) 7.6 (m,2), 7.4 (m,2), 7.0 (d,2), 4.4 (q,2), 3.8(s,3), 1.4 (t,3) ppm;

[0391] 2-chloro-6-(3-dimethylaminophenoxy)pyridine-4-carboxylic acid,ethyl ester; NMR (CDCl₃) 7.6 (s,1), 7.2 (m,2), 6.6 (d,1), 6.5 (m,2), 4.4(q,2), 3.0 (s,6), 1.4 (t,3) ppm;

[0392]4-benzyloxy-3-(4-(piperidin-1-yl)-3,5,6-trifluoropyridin-2-yl)benzonitrile;NMR (CDCl₃) 7.5 (m,2), 7.35 (m,3), 7.2 (m,2), 7.05 (d,1), 5.1 (s,2), 3.4(m,4), 1.75 (m,6) ppm;

[0393]4-benzyloxy-3-(4-(4-methylpiperazin-1-yl)-3,5,6-trifluoropyridin-2-yl)benzonitrile;NMR (CDCl₃) 7.5 (m,2), 7.35 (m,3), 7.2 (m,2), 7.05 (d,1), 5.1 (s,2), 3.4(m,4), 2.5 (m,4), 2.35 (s,3) ppm;

[0394]1-[(2-(5-cyano-2-methoxyphenoxy)-6-chloropyridin-4-yl)cacbonyl]-4-methylpiperazine;NMR (CDCl₃) 7.44 (dd,1), 7.3 (d,1), 6.95 (d,1), 6.9 (s,1), 6.74 (s,1),3.7 (s,3), 3.7 (m,2), 3.3 (m,2), 2.4 (m,2), 2.3 (m,2), 2.2 (s,3) ppm;

[0395]4-[(2-(5-cyano-2-benzyloxyphenoxy)-3,5,6-trifluoropyridin-4-yl)piperazine-1-aceticacid, ethyl ester; NMR (CDCl₃) 7.5 (m,2), 7.35 (m,3), 7.2 (m,2), 7.05(d,1), 5.1 (s,2), 4.2 (q,2), 3.5 (m,4), 3.3 (s,2), 2.75 (m,4), 1.3 (t,3)ppm;

[0396]3-[(3,5,6-trifluoro-4-methylpyridin-2-yl)oxy]-4-methoxybenzonitrile; NMR(CDCl₃) 7.6 (d,1), 7.4 (s,1), 7.0 (d,1), 3.8 (s,3), 2.4 (s,3) ppm;

[0397]3-[(3,5,6-trifluoro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (m,1), 7.2 (d,1), 7.3 (m,1), 7.1-7.2 (m,2), 4.7 (q,2),3.1 (s,3), 3.0 (s,3) ppm;

[0398]3-[(4-(1,3-difluoroprop-2-oxy)-3,5,6-trifluoropyridin-2-yl)oxy]-N,N-dimethylbenzamide;

[0399]N-(2-(5-cyano-2-methoxyphenoxy)-3,5,6-trifluoropyridin-4-yl)-N-methylglycine,ethyl ester;

[0400]N-(2-(3-cyanophenoxy)-3,5,6-trifluoropyridin-4-yl)-N-methylglycine,ethyl ester;

[0401]3-(4-(morpholin-1-yl)-3,5,6-trifluoropyridin-2-yl)oxy)-4-(benzyloxy)benzonitrile;

[0402] 2-chloro-6-(3-dimethylaminocarbonylphenoxy)pyridine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.59 (s,1), 7.46 (t,₁), 7.38 (s,1), 7.32(d,1), 7.21 (s,1), 7.2 (d,1), 4.42 (q,2), 3.05 (s,3), 2.88 (s,3), 1.20(t,3) ppm;

[0403] 3-[(6-fluoropyridin-2-yl)oxy]-N,N-dimethylbenzamide; NMR (CDCl₃)7.75 (q,1), 7.43 (m,1), 7.27 (m,1), 7.2 (m,2), 6.75 (m,1), 6.62, (d,1),3.1 (s,3), 3.0 (s,3) ppm;

[0404]4-[(2-(5-cyano-2-benzyloxyphenoxy)-3,5,6-trifluoropyridin-4-yl)oxy]-3-methoxybenzoicacid, ethyl ester; and

[0405]4-[(2-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-4-yl)oxy]-3-methoxybenzoicacid, ethyl ester.

PREPARATION 73-[(3,5-Difluoro-6-(5-dimethylamino-2-methylphenoxy)-4-methyl-pyridin-2-yl)oxybenzonitrile

[0406] A. In a manner similar to preparation 6, reaction of3-(3,5,6-trifluoro-4-methylpyridin-2-yl)benzonitrile (1.1 g, 4.4 mmol),5-dimethylamino-2-methylphenol (0.66 g, 4.4 mmol), and cesium carbonate(1.7 g, 5.2 mmol) in acetonitrile (10 mL) gave3-1(3,5-difluoro-6-(5-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]-benzonitrile;NMR (CDCl₃) 7.3 (m,4), 7.0 (d,1), 6.5 (d,1), 6.3 (s,1), 2.8 (s,6), 2.4(s,3), 2.0 (s,3) ppm.

[0407] B. In a similar manner, the following compounds were made:

[0408]3-[(3,5-difluoro-6-(3-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.1-7.5 (m,5), 6.9 (d,1), 6.65 (d,1), 6.3 (s,1), 2.6 (s,6),2.4 (s,3), 2.0 (s,3) ppm;

[0409]3,3′-[3,5-difluoro-4-methoxy-2,6-pyridinediylbis(oxy)bis(benzonitrile);NMR CDCl₃) 7.45 (m,4), 7.3 (m,4), 4.3 (s,3) ppm;

[0410]3-[(6-(3-cyanophenoxy)-3,5-difuoro-4-methylpyridin-2-yl)oxyl-4-methoxybenzenecarboxylicacid; NMR (CDCl₃) 7.9 (d,1), 7.7 (s,1), 7.2 (m,4), 6.95 (d,1), 3.85(s,3), 2.4 (s,3) ppm;

[0411]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-4,5-dimethoxybenzene-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.4 (s,1), 7.2-7.4 (m,5), 4.35 (q,2), 3.9(s,3), 3.8 (s,3), 2.4 (s,3) ppm;

[0412]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-4-methylbenzoicacid; NMR (CDCl₃) 7.75 (d,1), 7.55 (s,1), 7.1-7.3 (m,5), 2.4 (s,3), 2.2(s,3) ppm;

[0413]5-[6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylicacid, diethyl ester; NMR (CDCl₃) 8.45 (s,1), 7.85 (s,2), 7.25 (m,4), 4.4(q,4), 2.4 (s,3), 1.4 (t,6) ppm;

[0414]4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-3-methoxybenzoicacid; NMR (CDCl₃) 7.65 (dd,1), 7.62 (d,1), 7.33 (dt,1), 7.27 (dt,1),7.18 (m,2), 7.05 (d,1), 3.8 (s,3), 2.4 (s,3) ppm;

[0415] 3,3′-[3-nitro-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR(CDCl₃) 8.6 (d,1), 7.5 (m,4), 7.2 (m,4), 6.8 (d,1) ppm;

[0416]3-[(3,5-difluoro-6-(4-dimethylaminomethylphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.3 (m,5), 7.15 (m,1), 6.9 (m,2), 3.35 (s,2), 2.4 (s,3),2.15 (s,6) ppm;

[0417]3-[(3,5-difluoro-4-methyl-6-(3-(morpholin-4-yl)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.1-7.4 (m,5), 6.7 (d,1), 6.5 (s,1), 3.8 (m,4), 3.1 (m,4),2.4 (s,3) ppm;

[0418] 3-[(3,5-difluoro-6-(3-(2-(1H-imidazol-1-yl)-1-oxoethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.8 (d,1), 7.7 (s,1), 7.5 (m,2), 7.3 (m,5), 7.1 (s,1), 7.0(s,1), 5.45 (s,2), 2.4 (s,3) ppm;

[0419]4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoicacid; NMR (CDCl₃) 8.05 (d,2), 7.2-7.5 (m,4), 7.1 (d,2), 2.4 (s,3) ppm;

[0420] 3-[(3,5-difuoro-4-methyl-6-(3-((phenyl)oxomethyl)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.75 (d,2), 7.4-7.6 (m,6), 7.3 (m,5), 2.4 (s,3) ppm;

[0421]3-1(3,5-difluoro-6-(3-hydroxyphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.35 (m,4), 7.2 (t,1), 6.65 (dd,1), 6.6 (m,2), 5.65 (s,1),2.4 (s,3) ppm;

[0422]5-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-2-methoxy-benzonitrile;NMR (CDCl₃) 7.4 (d,1), 7.3 (s,1), 7.03 (t,1), 6.8 (d,1), 6.43 (d,1),6.25 (s,1), 6.18 (d,1), 3.68 (s,3), 2.85 (s,6), 2.45 (s,3) ppm;

[0423]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzeneaceticacid, ethyl ester; NMR (CDCl₃) 7.3 (m,5), 7.05 (d,1), 6.9 (m,2), 3.65(s,3), 3.6 (s,2), 2.4 (s,3) ppm;

[0424]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionicacid; NMR (CDCl₃) 7.3 (m,5), 7.05 (d,1), 6.85 (m,2), 2.9 (t,2), 2.6(t,2), 2.4 (s,3) ppm;

[0425]3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-2,6-dimethoxy-benzonitrile;NMR (CDCl₃) 7.3 (d,1), 7.0 (t,1), 6.55 (d,1), 6.4 (d,1), 6.2 (m,2), 3.9(s,3), 3.7 (s,3), 2.9 (s,6), 2.4 (s,3) ppm;

[0426]3-[(3,5-difluoro-6-(3-(2-hydroxyethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.2-7.4 (m,5), 7.0 (d,1), 6.85 (m,2), 3.75 (t,2), 2.8 (t,2),2.4 (s,3) ppm;

[0427]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzene-propionamide;NMR (CDCl₃) 7.45 (d,1), 7.1-7.4 (t,4), 7.0 (d,1), 6.85 (m,1), 6.8 (d,1),3.9 (s,3), 3.85 (s,3 ), 3.85 (m,2), 2.5 (t,2), 2.35 (s,3) ppm;

[0428]3-1(3,5-difluoro-6-(3-(hydroxymethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.3-7.5 (m,5), 7.2 (d,1), 7.1 (s,1), 6.95 (d,1), 4.7 (s,2),2.4 (s,3) ppm;

[0429]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.2-7.4 (m,5), 7.0 (m,1), 6.9 (m,2), 3.65 (s,2), 2.95 (s,6),2.35 (s,3) ppm;

[0430] 3-l(6-(3-cyanophenoxy)-3,5-difuoro-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl3) 7.35 (m,2), 7.25 (m,2), 7.2 (t,1), 7.0 (d,1), 6.85 (m,2),2.9 (t,2), 2.45 (t,2), 2.4 (s,3) ppm;

[0431]4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-α-hydroxybenzeneaceticacid; NMR (CDCl₃) 7.25 (m,6), 7.15 (s,1), 6.95 (m,1), 5.2 (s,1), 2.4(s,3) ppm;

[0432]3-[(3,5-difluoro-4-methyl-6-(3-(1-oxoethyl)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.75 (dt,1), 7.59 (m,1), 7.44 (t,1), 7.2-7.4 (m,5), 2.57(s,3), 2.40 (s,3) ppm;

[0433]3-[(3,5-difluoro-4-methyl-6-(3-(2-methyl-1-oxopropyl)phenoxy)pyridin-2-yl)oxy]-benzonitrile;NMR (CDCl₃) 7.75 (d,1), 7.6 (m,1), 7.45 (t,1), 7.2-7.4 (m,5), 3.45(m,1), 2..4 (s,3), 1.25 (m,6) ppm;

[0434]3-[(3,5-difluoro-4-methyl-6-(3-(1-methylethoxy)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.2-7.5 (m,5), 6.7 (d,1), 6.55 (m,2), 4.45 (m,1), 2.4 (s,3),1.3 (m,6) ppm;

[0435]α-acetoxy-4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-benzeneacetamide;NMR (CDCl₃) 7.3 (m,6), 7.15 (m,1), 7.0 (m,1), 6.1 (s,1), 2.9 (s,3), 2.85(s,3), 2.40 (s,3), 2.1 (s,3) ppm;

[0436]4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-α-ethoxybenzeneaceticacid, methyl ester; NMR (CDCl₃) 7.0-7.5 (m,8), 4.75 (s,1), 3.75 (s,3),3.35 (s,3), 2.4 (s,3) ppm;

[0437]3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-dimethylaminopyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (m,2), 7.1 (d,1), 6.95 (m,3), 3.8 (s,3), 3.1 (s,6), 3.05(s,3), 2.9 (s,3) ppm;

[0438]1-[(2-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-6-(3-dimethylaminocarbonyl-phenoxy)pyridin-4-yl]piperidine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.4 (d,1), 7.2 (m,2), 7.1 (d,1), 6.9(m,3), 4.15 (q,2), 3.75 (s,3), 3.7 (m,2), 3.25 (m,2), 3.1 (s,3), 2.95(s,3), 2.55 (m,1), 2.0 (m,4), 1.15 (t,3) ppm;

[0439]1-[(2-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-6-(3-dimethylaminocarbonyl-phenoxy)pyridin-4-yl]piperidine-3-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.4 (d,1), 7.3 (m,2), 7.1 (d,1), 6.9(m,3), 4.15 (q,2), 3.8 (m,1), 3.75 (s,3), 3.6 (m,1), 3.4 (m,1), 3.25(m,1), 3.1 (s,3), 2.9 (s,3), 2.7 (m,1), 2.15 (m,1), 1.8 (m,3), 1.15(t,3) ppm;

[0440]3-[(6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-4-(piperidin-1-yl)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (m,5), 7.2 (m,3), 7.1 (m,1), 6.95 (m,3), 5.1 (s,2), 3.4(m,4), 3.1 (s,3), 2.9 (s,3), 1.75 (m,6) ppm;

[0441]3-1(6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxyl-N,N-dimethylbenzamide;NMR (CDCl₃) 7.2 (m,9), 6.95 (m,3), 5.1 (s,2), 3.5 (m,4), 3.1 (s,3), 2.9(s,3), 2.6 (m,4), 2.4 (s,3) ppm;

[0442]4-[(2-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-6-(3-dimethylaminocarbonyl-phenoxy)pyridin-4-yl]piperazine-1-aceticacid, ethyl ester; NMR (CDCl₃) 7.3 (m,5), 7.15 (m,4), 6.95 (m,3), 5.1(s,2), 4.2 (q,2), 3.5 (m,4), 3.3 (s,2), 3.1 (s,3), 2.8 (s,3), 2.75(m,4), 1.3 (t,3) ppm;

[0443]1-[(2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminocarbonylphenoxy)pyridin-4-yl)carbonyl]-4-methylpiperazine;NMR (CDCl₃) 7.4 (dd,1), 7.27 (m,2), 7.16 (m,1), 7.0 (m,2), 6.9 (d,1),6.63 (s,1), 6.55 (s,1), 3.8 (m,2), 3.8 (s,3), 3.5 (m,2), 3.1 (s,3), 2.9(s,3), 2.5 (m,2), 2.4 (m,2), 2.4 (s,3) ppm;

[0444]1-[(2-(5-cyano-2-methoxyphenoxy)-6-chloropyridin-4-yl)carbonyl]-4-methylpiperazine;NMR (CDCl₃) 7.44 (dd,1), 7.3 (d,1), 6.95 (d,1), 6.9 (s,1), 6.74 (s,1),3.7 (s,3), 3.7 (m,2), 3.3 (m,2), 2.4 (m,2), 2.3 (m,2), 2.2 (s,3) ppm;

[0445]2-(5-cyano-2-methoxyphenoxy)-6-(3-(imidazol-1-yl)phenoxy)pyridine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.8 (s,1), 7.3 (m,3), 7.2 (m,5), 7.0(m,2), 6.7 (d,1), 4.4 (q,2), 3.7 (s,3), 1.4 (t,3) ppm;

[0446]2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminophenoxy)pyridine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.4 (d,1), 7.3 (s,1), 7.2 (s,1), 7.1(t,1), 7.0 (s,1), 6.8 (d,1), 6.5 (d,1), 6.3 (m,2), 4.4 (q,2), 3.7 (s,3),2.8 (s,6), 1.4 (t,3) ppm;

[0447]3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 8.00 (bs,1), 7.40 (dt,1), 7.25 (t,1), 7.21 (dt,1), 7.08(bd,1), 6.91 (bs,1), 6.87 (td,1), 3.74 (s,3), 2.92 (s,3), 2.85 (s,3),2.39 (s,3) ppm;

[0448]3-[(6-(2-amino-5-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.5 (t,1), 7.2-7.0 (m,5), 6.6 (d,1), 4.6 (s,2), 3.1 (s,3),2.9 (s,3), 2.0 (s,3) ppm;

[0449]3-[(6-(2-amino-5-cyanophenoxy)-3,5-difluoro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.3 (dd,1), 7.2 (d,1), 7.1 (m,2), 7.0-7.1 (m,2), 6.6 (d,1),4.8 (q,2), 4.6 (s,2), 3.1 (s,3), 2.9 (s,3) ppm;

[0450]3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]-N,N-dimethylbenzamide; NMR (CDCl₃) 7.4 (dd,1), 7.3 (d,1), 7.2(t,1), 7.1 (d,1), 6.9-7.0 (m,2), 6.9 (d,1), 4.7 (q,2), 3.7 (s,3), 3.1(s,3), 2.9 (s,3) ppm; and

[0451]3-[(6-(5-cyano-2-methoxyphenoxy)-4-(1,3-difluoroprop-2-oxy)-3,5-difluoropyridin-2-yl)oxyl-N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (dd,1), 7.3 (d,1), 7.2 (t,1), 7.1 (d,1), 6.9-7.0 (m,2),6.9 (d,1), 5.0 (m,1), 4.9 (d,2), 4.7 (d,2), 3.7 (s,3), 3.1 (s,3), 2.9(s,3) ppm.

PREPARATION 8 4-(6-Fluoropyridin-2-yl)oxy-3-methoxybenzonitrile

[0452] A. To 4-hydroxy-3-methoxybenzonitrile (2.6 g, 17 mmol) in DMSO(15 mL) was added sodium hydride (0.44 g, 18 mmol) and2,6-difluoropyridine (1.0 g, 8.7 mmol). After heating at 100° C. for 18hours the reaction was partitioned with ethyl acetate and water. Theorganic layer was separated, washed with water, dried (Na₂SO₄), and thesolvent was removed in vacuo to give4-(6-fluoropyridin-2-yl)oxy-3-methoxybenzonitrile (1.3 g); NMR (CDCl₃)7.8 (q,1), 7.35 (m,1), 7.25 (m,2), 6.85 (d,1), 6.65 (m,1), 3.85 (s,3)ppm.

[0453] B. In a similar manner, the following compounds were made:

[0454] 3-[(4-methyl-3,5,6-trifluoropyridin-2-yl)amino]benzonitrile; NMR(CDCl₃) 8.05 (s,1), 8.95 (d,1), 7.6 (d,1), 7.45 (t,1), 7.25 (s,1), 2.3(s,3) ppm;

[0455] 2-chloro-6-(3-cyanophenoxy)pyridine-4-carboxylic acid, ethylester, NMR (CDCl₃) 7.80-7.38 (m,6), 4.41 (q,2), 1.92 (t,3) ppm;

[0456]2-chloro-6-(5-cyano-2-methoxyphenoxy)-N,N-dimethylpyridine-4-carboxamide;NMR (CDCl₃) 7.2 (m,5), 3.84 (s,3), 3.13 (s,3), 2.95 (s,3) ppm; and

[0457] 2-chloro-6-(5-cyanophenoxy)-N,N-dimethylpyridine-4-carboxamide;NMR (CDCl₃) 7.45 (m,3), 7.08 (s,1), 6.87 (s,1), 6.67 (s,1), 3.14 (s,3),3.00 (s,3) ppm.

PREPARATION 9 2-Methoxy-3′,4-[2,6-pyridinediylbis(oxy)]benzonitrile

[0458] A. To 4-(6-fluoropyridin-2-yl)oxy-3-methoxybenzonitrile (0.65 g,2.7 mmol) in DMSO (15 mL) was added 3-cyanophenol (0.32 g, 0.91 mmol)and sodium hydride (0.070 g, 2.9 mmol). After heating at 140° C. for 2days, the reaction was poured into water and the precipitate wasfiltered off. The solid was chromatographed to give2-methoxy-3′,4-[2,6-pyridinediylbis(oxy)]benzonitrile; NMR (CDCl₃) 7.75(t,1), 7.2-7.5 (m,6), 7.1 (d,1), 6.7 (d,1), 6.65 (d,1), 3.8 (s,3) ppm.

[0459] B. In a similar manner, the following compounds were made:

[0460] 3,3′-bis(methoxy)-4,4′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR(CDCl₃) 7.75 (t,1), 7.2 (d,2), 7.1 (m,4), 6.65 (d,2), 3.75 (s,6) ppm;

[0461]3-[(3,5-difluoro-6-(3-ethylamino-4-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzonitriie;NMR (CDCl₃) 7.3 (m,4),6.95 (d,1), 6.25 (m,2), 3.45 (br s,1), 3.1 (q,2),2.4 (s,3), 2.1 (s,3), 1.3 (t,3) ppm;

[0462] 3,4′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃) 7.8(t,1), 7.6 (d,2), 7.2-7.5 (m,4), 7.14 (d,2), 6.7 (d,2) ppm;

[0463]3-[(6-[(3-cyanophenyl)amino]-3,5-difluoro-4-methylpyridin-2-yl)oxybenzonitrile;NMR (CDCl₃) 7.65 (m,2), 7.5 (m,2), 7.2-7.4 (m,4), 2.4 (s,3) ppm;

[0464]3-[6-(3-cyanophenyl)amino-3,5-difluoro-4-methylpyridin-2-yl(methylamino)]-benzonitrile;NMR (CDCl₃) 7.1-7.5 (m,9), 3.4 (s,3), 2.3 (s,3) ppm;

[0465] 3-[(3,5-difluoro-4-methyl-6-(pyridin-3-yloxy)pyridin-2-yl)oxy]benzonitrile; NMR (CDCl₃) 8.4 (m,2), 7.35 (m,4), 7.25(m,4), 2.4 (s,3) ppm;

[0466] 3-[(3,5-difluoro-4-methyl-6-phenoxypyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.25-7.5 (m,6), 7.2 (t,1), 7.0 (d,2), 2.4 (s,3) ppm;

[0467]3-[(3,5-difluoro-6-(4-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.25-7.5 (m,4), 6.95 (d,2), 6.65 (d,2), 2.95 (s,6), 2.4(s,3) ppm;

[0468] 3-[(6-(3,5-difluoro-6-(3-(1H-imidazol-1-yl)phenoxy)-4-methylpyridin-2-yl)oxy]-benzonitrile; NMR(CDCl₃) 7.75 (s,1), 7.4 (t,1), 7.1-7.3 (m,7), 7.03 (m,2), 2.4 (s,3) ppm;

[0469]3-[(3,5-difluoro-4-methyl-6-(3-nitrophenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 8.03 (d,1), 7.85 (s,1), 7.5 (t,1), 7.4 (m,3), 7.3 (m,2), 2.4(s,3) ppm;

[0470]3-[(6-(3-aminophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.35 (m,4), 7.05 (t,1), 6.45 (d,1), 6.35 (m,2), 2.4 (s,3)ppm;

[0471]N-[3-((6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy)phenoxylacetamide;NMR (CDCl₃) 7.55 (m,2), 7.2-7.4 (m,5), 7.0 (d,1), 6.75 (d,1), 2.4 (s,3),2.2 (s,3) ppm;

[0472]3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;

[0473]3-[(3,5-difluoro-6-(3-(2-(dimethylamino)ethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;

[0474]1-[3-((6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy)phenyl]urea;

[0475]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoicacid, ethyl ester;

[0476]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzenecarboxamide;

[0477]3-[(3,5-difluoro-6-(3-ethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;

[0478]3-[(6-(3-diethylaminophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;

[0479] 3-[(3,5-difluoro-4-methyl-6-(3-phenylaminophenoxy)pyridin-2-yl)oxybenzonitrile;

[0480]3-[(6-(3-chlorophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.4 (m,2), 7.2-7.33 (m,3), 7.13 (ddd,1), 7.0 (t,1), 6.91(ddd,1), 2.4 (s,3) ppm;

[0481]3-[(3,5-difluoro-4-methyl-6-(3-trifluoromethylphenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.42 (m,3), 7.33 (t,1), 7.15-7.3 (m,4), 2.4 (s,3) ppm;

[0482]3-[(3,5-difluoro-6-(3-methoxyphenoxy)-4-methylpyridin-2-yl)oxy)benzonitrile;NMR (CDCl₃) 7.25-7.42 (m,5), 6.72 (ddd,1), 6.6 (m,1), 6.58 (m,1), 3.8(s,3), 2.4 (s,3) ppm;

[0483]3-[(3,5-difluoro-6-(3-fluorophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.35-7.45 (m,2), 7.2-7.33, (m,3), 6.85 (m,2), 6.73 (dt,1),2.4 (s,3) ppm;

[0484]3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxyl-4-methylbenzonitrile;NMR (CDCl₃) 7.28 (m,1), 7.26 (s,1), 7.2 (m,2), 7.12 (t,1), 6.48 (dd,1),6.28 (m,2), 2.88 (s,6), 2.38 (s,3), 2.21 (s,3) ppm;

[0485]4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)-oxy]benzonitrile;NMR (CDCl₃) 7.2 (m,3), 6.66 (d,1), 6.54 (d,1), 6.35 (m,2), 4.28 (s,2),2.91 (s,6), 2.37 (s,3) ppm;

[0486]3-[(6-(5-cyano-2-methoxyphenoxy)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.7 (t,1), 7.4 (dd,1), 7.3 (d,1), 7.27 (d,1), 7.15 (dt,1),7.0 (m,2), 6.9 (d,1), 6.66 (d,1), 6.57 (d,1), 3.8 (s,3), 3.1 (s,3), 2.9(s,3) ppm;

[0487]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoicacid, ethyl ester; NMR (CDCl₃) 7.3 (m,6), 6.7 (s,1), 4.3 (q,2), 2.4(s,3), 1.5 (t,3) ppm;

[0488]3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoicacid; NMR (CDCl₃) 7.4 (d,1), 7.3 (m,2), 7.1 (s,1), 6.8 (d,1), 6.6 (s,1),5.6 (s,1), 4.4 (q,2), 3.8 (s,3), 2.4 (s,3), 1.4 (t,3) ppm;

[0489]2-13-cyanophenoxy)-6-(5-cyano-2-(benzyloxy)phenoxy)pyridine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.62-7.02 (m,12 ), 5.16 (s,2H), 4.42(q,2), 1.41 (t,3) ppm;N-12-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoropyridin-4-yl]-N-methylglycine,ethyl ester;

[0490]N-[2-(5-cyanophenoxy)-6-(3-dimethylaminophenoxy)-3,5-difluoropyridin-4-yl]-N-methylglycine,ethyl ester;

[0491] 3-[(6-(5-cyano-2-benzyloxyphenoxy)-3,5difluoro-4-(morpholin-1-yl)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;

[0492]2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminocarbonylphenoxy)pyridine-4-carboxylicacid, methyl ester; NMR (CDCl₃) 7.2 (m,9), 3.92 (s,3), 3.70 (s,3), 3.10(s,3), 2.88 (s,3) ppm;

[0493]2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminocarbonylphenoxy)-N,N-dimethylpyridine-4-carboxamide;NMR (CDCl₃) 7.1 (m,7), 6.55 (s,1), 6.48 (s,1), 3.65 (s,3), 2.95 (m,12)ppm;

[0494]2-(3-cyanophenoxy)-6-(3-dimethylaminocarbonylphenoxy)-N,N-dimethylpyridine-4-carboxamide;NMR (CDCl₃) 7.16 (m,8), 6.57 (s,1), 6.53 (s,1), 2.95 (m,12) ppm; and

[0495]4-[(2-(3-aminophenoxy)-6-(5-cyano-2-phenylmethoxyphenoxy)-3,5-difluoropyridin-4-yl)oxy]-3-methoxybenzoicacid, ethyl ester.

PREPARATION 10 2,6-Bis(3-cyanophenoxy)-N-methylpyridine-4-carboxamide

[0496] A. To 2,6-bis(3-cyanophenoxy)pyridine-4-carboxylic acid, ethylester (1.6 g, 4.0 mmol) in tetrahydrofuran/water (50 mL, 1/1) was addedlithium hydroxide (0.85 g, 20 mmol). After stirring for 1.5 hours thereaction was partitioned with 1M HCl and ethyl acetate. The organiclayer was separated, dried (MgSO₄), and the solvent was removed invacuo. The residue was dissolved in methylene chloride (50 mL) andthionyl chloride (2.4 g, 20 mmol) was added. After stirring for 2 hoursthe solvent was removed in vacua. The residue was dissolved in methylenechloride/water (30/10 mL) and methylamine hydrochloride (0.090 g, 1.3mmol) and potassium carbonate (0.46 g, 3.3 mmol) were added. The organiclayer was separated, washed with brine, dried (MgSO₄), and the solventremoved in vacuo to give2,6-bis(3-cyanophenoxy)-N-methylpyridine-4-carboxamide; NMR (CDCl₃) 7.5(m,4), 7.3 (m,4), 7.0 (s,2), 6.25 (br s,1), 3.1 (d,3) ppm.

[0497] B. In a similar manner, the following compounds were made:

[0498] 2,6-bis(3-cyanophenoxy)-N-methylpyridine-3-carboxamide; NMR(CDCl₃) 7.8 (d,1), 7.4-7.6 (m,5), 7.1-7.3 (m,4), 6.8 (d,1), 3.1 (d,3)ppm;

[0499] N-[[2,6-bis(3-cyanophenoxy)pyridin-3-yl]oxomethyl]glycine, ethylester; NMR (CDCl₃) 8.65 (d,1), 8.1 (t,1), 7.2-7.6 (m,8), 6.8 (d,1), 4.3(m,4), 1.3 (t,3} ppm; and

[0500] 2,6-bis(3-cyanophenoxy)-N,N-dimethylpyridine-4-carboxamide; NMR(CDCl₃) 7.85 (d,1), 7.45 (m,4), 7.25 (m,4), 6.75 (d,1), 3.2 (s,3), 3.1(s,3) ppm.

PREPARATION 113-[(6-(3-Cyanophenyl)methylamino-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile

[0501] A. To3-[(6-(3-eyanophenyl)amino-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzonitrile(0.10 g, 0.28 mmol) in acetonitrile (10 mL) was added iodomethane (0.20g, 1.4 mmol) and sodium hydride (0.055 g, 1.4 mmol). After stirring for18 hours the reaction was partitioned with water and ethyl acetate. Theorganic layer was separated, dried (Na₂SO₄), and the solvent was removedin vacuo. Chromatography of the residue on silica gel with ethylacetate/hexane (1/3) as eluent gave3-[(6-(3-cyanophenyl)-methylamino-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzonitrile;NMR (CDCl₃) 7.4 (m,5), 7.25 (m,1), 7.1 (m,2), 3.25 (s,3), 2.3 (s,3) ppm.

[0502] B. In a similar manner, the following compounds were made:

[0503]3-(4-methyl-3,5,6-trifluoropyridin-2-yl)_(m)ethylaminobenzonitrile; NMR(CDCl₃) 7.35 (t,1), 7.3 (m,1), 7.2 (m,2), 3.4 (s,3), 2.3 (s,3) ppm; and

[0504]3,3′-[3,5-difluoro-4-methyl-2,6-pyridinediylbis(methylamino);bis(benzonitrile);NMR (CDCl₃) 7.1-7.5 (m,8), 3.4 (s,6), 2.3 (s,3) ppm.

PREPARATION 123-[(6-(3-Cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoicAcid, Ethyl Ester

[0505] A. Toacetonitrile (5 mL) wasadded3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoicacid, ethyl ester (0.20 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94mmol), and iodomethane (0.13 g, 0.94 mmol). After stirring for 15 hoursthe mixture was partitioned with ethyl acetate and water. The organiclayer was dried (MgSO₄) and the solvent was removed in vacuo to give3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl-pyridin-2-yl)oxy]-5-methoxybenzoicacid, ethyl ester; NMR (CDCl₃) 7.3 (m,6), 6.8 (s,1), 4.4 (q,2), 3.8(s,3), 2.4 (s,3), 1.4 (t,3) ppm.

[0506] B. In a similar manner, the following compound was made:

[0507]3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoicacid, ethyl ester; NMR (CDCl₃) 7.4 (d,1), 7.3 (m,2), 7.1 (s,1), 6.8(d,1), 6.6 (s,1), 4.4 (q,2), 3.8 (s,3), 3.7 (s,3), 2.4 (s,3), 1.4 (t,3)ppm.

PREPARATION 135-[(6-(3-Cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxybenzene-1,3-dicarboxylicacid

[0508] A. To5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylicacid, diethyl ester (0.97 g, 2.0 mmol) in tetrahydrofuran/water (20 mL,1/1) was added lithium hydroxide (0.42 g, 10 mmol). After heating at 60°C. for 90 minutes, the material was partitioned between ethyl acetateand 2N HCl. The organic layer was separated, dried (MgSO₄), and thesolvent removed in vacuo to give5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl-pyridin-2-yl)oxy]benzene-1,3-dicarboxylicacid; NMR (DMSO) 8.25 (s,1), 7.85 (s,2), 7.4-7.7 (m,3), 7.3 (m,3), 2.4(s,3) ppm.

[0509] B. In a similar manner, the following compounds were made:

[0510]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-2,3-dimethoxybenzenecarboxylicacid; NMR (DMSO-d₆) 7.95 (s,1), 7.1-7.7 (m,5), 3.85 (s,3), 3.6 (s,3),2.4 (s,3) ppm;

[0511]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoic acid; and

[0512]3-1(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoicacid.

PREPARATION 143-[(6-(3-Cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-4-methoxybenzamide

[0513] A. To3-[(6-(3-cyanophenoxy)-3,5-difluoro74-methylpyridin-2-yl)oxy]-4-methoxybenzoicacid (0.47 g, 1.1 mmol) in tetrahydrofuran (12 mL) was added 1,1′-carbonyldiimidazole (0.22 g, 1.4 mmol) and stirred at ambienttemperature for 3 hours. Then dimethylamine (aq, 0.077 g, 1.7 mmol) wasadded. After stirring for 12 hours the solution was partitioned betweenwater and ethyl acetate. The organic layer was separated, dried (MgSO₄),and the solvent was removed in vacuo. Chromatography on silica gel withethyl acetate/hexane (1/8) as eluent gave3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-NN-dimethyl-4-methoxybenzamide;NMR (CDCl₃) 6.9-7.4 (m,7), 3.8 (s,3), 3.0 (br,6), 2.4 (s,3) ppm.

[0514] B. In a similar manner, the following compounds were made:

[0515]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-4-methoxybenzamide;NMR (CDCl₃) 7.3 (m,2), 7.2 (m,3), 7.15 (d,1), 6.95 (s,1), 3.05 (br,3),2.85 (br,3), 2.4 (s,3), 2.15 (s,3) ppm;

[0516]5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N,N′,N′-tetraethylbenzene-1,3-dicarboxamide;NMR (CDCl₃) 7.9 (s,1), 7.65 (s,2), 7.1-7.5 (m,4), 3.45 (br,4), 3.15(br,4), 2.4 (s,3), 1.25 (br,6), 1.05 (br,6) ppm;

[0517]5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-2,3-dimethoxy-N,N-dimethylbenzamide;NMR (DMSO-d₆) 7.95 (m,1), 7.1-7.7 (m,5), 3.9 (s,3), 3.65 (s,3), 3.4(s,3), 3.15 (s,3), 2.4 (s,3) ppm;

[0518] 5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N,N′,N′-tetramethylbenzene-1,3-dicarboxamide; NMR (CDCl₃) 7.7(s,2), 7.1-7.5 (m,5), 3.1 (m,6), 2.9 (s,3), 2.85 (s,3), 2.4 (s,3) ppm;

[0519]4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-3-methoxy-N,N-dimethylbenzamide;NMR (CDCl₃) 7.7 (s,1), 7.2-7.4 (m,3), 7.1 (s,1), 7.05 (m,1), 6.95 (d,1),3.8 (s,3), 3.1 (s,3), 3.0 (s,3), 2.4 (s,3) ppm;

[0520]1-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl)pyridin-2-yl)oxybenzoyl]pyrrolidine;NMR (CDCl₃) 7.2-7.5 (m,6), 7.2 (s,1), 7.1 (d,1), 3.65 (m,2), 3.3 (m,2),2.4 (s,3), 1.8-2.1 (m,4) ppm;

[0521]1-[3-[(6-(3-yanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoylmorpholine;

[0522]4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-benzamide;NMR (CDCl₃) 7.2-7.6 (m,6), 7.05 (d,2), 3.2 (br,3), 3.0 (br,3), 2.4 (s,3)ppm;

[0523]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N-methylbenzenecarboxamide;

[0524]1-[3-l(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoyl]-4-ethylpiperazine;

[0525]1-[3-(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoyl]piperidine;

[0526] 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N-methyl-N-(phenyl-methyl)benzamide;

[0527]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N-methyl-N-[2-(pyridin-2-yl)ethyl]benzamide;

[0528] 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N-ethyl-N-methylbenzamide;

[0529]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-diethylbenzamide;

[0530]N-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoyl]-β-alanine,ethyl ester;

[0531]3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-5-methoxybenzamide;NMR (CDCl₃) 7.4 (m,2), 7.3 (m,2), 6.7 (s,1), 6.6 (s,2), 3.8 (s,3), 3.0(s,3), 2.8 (s,3), 2.4 (s,3) ppm; and

[0532]3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-5-methoxybenzamide;NMR (CDCl₃) 7.4 (d,1), 7.3 (s,1), 6.9 (d,1), 6.6 (d,1), 6.5 (d,1), 3.8(s,6), 3.1 (s,3), 2.9 (s,3), 2.4 (s,3) ppm.

PREPARATION 15 3,3′-[3-Amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile)

[0533] A. To 3,3′-[3-nitro-2,6-pyridinediylbis(oxy)]bis(benzonitrile)(18.5 g, 50 mmol) dissolved in ethanol/ethyl acetate (500 mL, 2/3) wasadded 10% palladium on carbon (1.8 g). After subjecting the mixture tohydrogen at 15 psi for 2 hours, the reaction was suction filteredthrough celite. The solvent was removed in vacuo to give3,3′-[3-amino-2,6-pyridinediylbis(oxy)]-bis(benzonitrile); NMR (CDCl₃)7.5 (m,7), 7.2 (m,2), 6.6 (d,1), 3.8 (br,2) ppm.

PREPARATION 16 N-[2,6-Bis(3-cyanophenoxy)pyridin-3-yl]benzamide

[0534] A. To3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile)(1.0 g,2.9 mmol) dissolved in acetonitrile (50 mL) was added benzoylchloride (0.50 g, 3.5 mmol) and triethylamine (0.45 g, 0.60 mmol). Afterstirring for 3 hours, the reaction was partitioned between ether andwater. The organic layer was separated, washed with water, saturatedaqueous sodium bicarbonate, and brine, dried (MgSO₄), and the solventwas removed in vacuo. Chromatography on silica gel with ethylacetate/hexane (1/3) as eluentgaveN-[2,6-bis(3-cyanophenoxy)-pyridin-3-yl]benzamide; NMR (CDCl₃) 8.95(d,1), 8.25 (s,1), 7.9 (d,1), 7.2-7.7 (m,12), 6.8 (d,1) ppm.

[0535] B. In a similar manner, the following compounds were made:

[0536] N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]acetamide; NMR (CDCl₃)8.65 (d,1), 7.6 (s,1), 7.1-7.6 (m,8), 6.7 (d,1), 2.3 (s,3) ppm;

[0537] N-[[(2,6-bis(3-cyanophenoxy)pyridin-3-yl)amino]carboxy]glycine,ethyl ester; NMR (CDCl₃) 8.5 (d,1), 7.2-7.5 (m,8), 7.15 (s,1), 6.6(d,1), 5.7 (m,1), 4.2 (q,2), 4.1 (m,2), 1.25 (d,3) ppm;

[0538] N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]methanesulfonamide; NMR(CDCl₃) 8.0 (d,1), 7.45 (m,4), 7.25 (m,4), 6.75 (d,1), 6.6 (s,1), 3.1(s,3) ppm; and

[0539]N-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxylphenyl]methanesulfonamide;NMR (CDCl₃) 8.8 (d,1), 7.65 (m,2), 7.35 (m,4), 7.05 (m,2), 2.95 (s,3),2.3 (s,3) ppm.

PREPARATION 17 N-[2,6-Bis(3-cyanophenoxy)pyridin-3-yl]-N′-phenylurea

[0540] A. To 3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile)(3.0 g, 8.7 mmol) dissolved in acetonitrile (100 mL) was added phenylisocyanate (1.1 g, 9.5 mmol). After refluxing for 4 hours, the reactionwas partitioned between ether and water. The organic layer wasseparated, washed with water, saturated aqueous sodium bicarbonate, andbrine, dried (MgSO₄), and the solvent was removed in vacuo.Chromatography on silica gel with ethyl acetate/hexane (1/4) as eluentgave material which was crystallized from ethyl acetate/hexane togiveN-[2,6-bis(3-cyano-phenoxy)pyridin- 3-yl]-N′-phenylurea; NMR (CDCl₃)8.65 (d,1), 7.4 (m,8), 7.1-7.3 (m,6), 6.8 (s,1), 6.7 (d,1) ppm.

[0541] B. In a similar manner, the following compound was made:

[0542] N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]-N′-methylurea; NMR(CDCl₃) 8.65 (d,1), 7.5 (m,4), 7.25 (m,4), 6.8 (s,1), 6.7 (d,1), 2.9(d,3) ppm.

PREPARATION 183-[(6-(3-Cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzenepropionicAcid, Methyl Ester

[0543] To3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-propionicacid(0.50 g, 1.2 mmol) in methylene chloride (20 mL) was added methyl iodide(0.26 g, 1.8 mmol) and diazabicycloundecane (2.8 g, 1.8 mmol). Afterstirring for 15 hours, the solution was concentrated in vacuo andchromatographed on silica gel with ethyl acetate/hexane (1/4) to give3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionicacid, methyl ester; NMR (CDCl₃) 7.3 (m,5), 7.05 (d,1), 6.85 (m,2), 3.68(s,3), 2.9 (t,2), 2.55 (t,2), 2.4 (s,3) ppm.

PREPARATION 19 4,4′-[1,3-Phenylenebis(oxy)]benzonitrile

[0544] To DMSO (6 mL) was added resorcinol (1.1 g, 10 mmol),4-fluorobenzonitrile (2.4 g, 20 mmol) and potassium carbonate (2.4 g, 17mmol). After heating in an oil bath at 100° C. for 16 hours the reactionmixture was partitioned with water and ethyl acetate. The organic layerwas separated, washed with 1N sodium hydroxide, water, brine, dried(sodium sulfate) and concentrated in vacuo. Chromatography on silica gelwith methylene chloride/hexane (20/1) as eluent gave4,4′-[1,3-phenylenebis(oxy)]benzonitrile; NMR (CDCl₃) 7.64 (d,4), 7.43(t,1), 7.06 (d,4), 6.82 (dd,2), 6.80 (t,1) ppm.

PREPARATION 204-[(2-(3-(Guanidino)phenoxy)-6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoropyridin-4-yl)oxy]-3-methoxybenzoicAcid, Ethyl Ester

[0545] To ethanol (15 mL) was added4-[[2-(3-aminophenoxy)-6-(5-cyano-2-phenyl-methoxyphenoxy)-3,5-difluoropyridin-4-yl]oxy]-3-methoxybenzoicacid, ethyl ester (0.50 g, 0.80 mmol), cyanamide (0.60 9, 14 mmol), and6M hydrochloric acid (0.7 mL). After refluxing for 19 hours, cyanamide(0.60 g, 14 mmol) and 6M hydrochloric acid (0.7 mL) was added andrefluxing was continued for 4 hours. The reaction mixture wasconcentrated in vacuo and purified by HPLC to give4-[[2-[3-(guanidino)phenoxy)-6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-pyridin-4-yl)oxy]-3-methoxy]benzoic acid, ethyl ester.

EXAMPLE 1 3,3′-[2,6-Pyridinediylbis(oxy)]bis(benzamidine),Dihydrochloride

[0546] A. To 3,3′-[2,6-pyridinylbis(oxy)]bis(benzonitrile) (0.2 g, 0.7mmol) slurried in ethanol (6 mL) cooled in a dry ice/isopropanol bathwas bubbled HCl (g). After the solution was saturated the reaction flaskwas sealed and allowed to warm to ambient temperature and stir for 18hours. The solvent was removed in vacuo and the residue was trituratedwith ether. The ether was removed by decantation and the residue wasdissolved in ethanol (6 mL). The solution was cooled in a dryice/isopropanol bath and ammonia (g) was bubbled in. The reaction flaskwas sealed and heated to 50° C. for 2 hours. The solvent was removed invacuo and the residue was recrystallized from 5M HCl to give3,3′-[2,6-pyridinediylbis(oxy)]bis(benzamidine), dihydrochloride as asolid; m.p. 160° C. (decom); NMR (DMSO-d₆) 9.45 (s,4), 9.3 (s,4), 8.02(t,1), 7.4-7.8 (m,8), 6.90 (d,2) ppm.

[0547] B. In a similar manner, the following compounds were made:

[0548] 4,4′-[2,6-pyridinediylbis(oxy)]bis(benzamidine), dihydrochloride;NMR (DMSO-d₆) 9.4 (s,4), 9.2 (s,4), 8.1 (t,1), 7.95 (d,4), 7.40 (d,4),6.96 (d,2) ppm;

[0549]3,3′-bis(methoxy)-4,4′-[2,6-pyridinediylbis(oxy)]bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.5 (br s,4), 9.2 (br s,4), 7.9 (t,1),7.7 (s,2), 7.5 (d,2), 7.3 (d,2), 6.7 (d,2), 3.85 (s,6) ppm;

[0550] 4-[(6-(3-amidinophenoxy)pyridin-2-yl)oxy]-3-methoxy]benzamidine,dihydrochloride; NMR (DMSO-d₆) 9.7 (s,2), 9.55 (s,2), 9.4 (br s,4), 7.95(t,1), 7.75 (s,1), 7.3-7.7 (m,6), 6.85 (d, 1), 6.75 (d,1), 3.9 (s,3)ppm;

[0551]3-[(3,5-difluoro-6-(3-ethylamino-4-methylphenoxy)-4-methylpyridin-2-yl)oxy]-benzamidine,dihydrochloride; NMR (DMSO-d₆) 9.4 (s,2), 9.2 (s,2), 7.6 (m,2), 7.55(t,1), 7.45 (m,1), 7.3 (m,2), 7.15 (dd,1), 3.2 (q,2), 2.4 (s,3), 2.35(s,3), 1.2 (t,3) ppm;

[0552] 3,3′-[3-trifluoromethyl-2,6-pyridinediylbis(oxy)Ibisbenzamidine), dihydrochloride; NMR (DMSO-d₆) 9.4 (s,4), 9.2 (s,4), 8.3(d,1), 7.7 (m,4), 7.6 (d,4), 7.0 (m,1) ppm;

[0553] 3,4′-[2,6-pyridinediylbis(oxy)]bis(benzamidine), dihydrochloride;NMR (DMSO-d₆) 9.4 (br s,8), 8.1 (t,1), 7.9 (d,2), 7.5-7.8 (m,4), 7.40(d,2), 6.95 (m,2) ppm;

[0554] 3,3′-[3-methylaminocarbonylamino-2,6-pyridinediylbis(oxy)]bisbenzamidine), dihydrochloride; m.p. 205-206° C.;

[0555]4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-carboxy-pyridin-2-yl)oxy]benzamidine,hydrochloride; NMR (DMSO-d₆) 9.2 (s,2), 9.0 (s,2), 7.9 (t,1), 7.78(dd,1), 7.68 (m,1), 7.36 (t,1), 7.26 (d,1), 7.15 (d,1), 7.05 (m,1), 7.02(m,1), 6.75 (d,1), 6.7 (d,1), 3.8(s,3), 2.95(s,3), 2.8 (s,3) ppm;

[0556]4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-methyl-piperazinoyl)pyridin-2-yl)oxy]benzamidine,dihydrochloride;

[0557] 3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(ethoxycarbonylmethyl)amino) pyridin-2-yl)oxy]benzamidine, ethyl ester,hydrochloride; NMR (DMSO-d₆) 9.3 (s,2), 9.2 (s,2), 7.5 (m,4), 7.2 (t,1),6.7 (m,2), 6.5 (d,1), 4.2 (s,2), 3.2 (s,3), 2.9 (s,6) ppm;

[0558]4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(dimethylamino-carbonyl)pyridin-2-yl)oxy]benzamidine,hydrochloride;

[0559]4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonyl)-pyridin-2-yl)oxy]benzamidine,hydrochloride; and

[0560]4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonyl)pyridin-2-yl)oxy]benzamidine,hydrochloride.

[0561] C. In a similar manner, reaction of3,3′-[3,5-difluoro-4-methyl-2,6-pyridinediyl-bis(oxy)]bis(benzonitrile)gave3,3′-[3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy)]bis(benzamidine);which was purified by HPLC on a C18 Dynamax column with a 20-80%acetonitrile in water gradient with 0.1% trifluoroacetic acid to givethecompound as a pure trifluoroacetic acid salt; m.p. >210° C.; NMR(DMSO-d₆) 9.3 (br s,8), 7.6 (m,4), 7.54 (m,4), 2.4 (m,3) ppm.

[0562] D. In a similar manner, the following compounds were made:

[0563] 3,3 ′-(3,5-dichloro-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.2 (br s,8), 8.6 (s,1),7.4-7.7 (m,8) ppm;

[0564] 4,4′-(3,5-dichloro-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.25 (s,4), 9.0 (s,4), 8.58(s,1), 7.8 (d,4) 7.4 (d,4) ppm;

[0565] 3,3′-(4-ethoxycarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.55 (br s,4), 9.4 (br s,4),7.65 (m,4), 7.6 (m,4), 7.2 (s,2), 4.4 (q,2), 1.4 (t,3) ppm;

[0566] 3,3′-(3-ethoxycarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine), trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (brs,4), 9.1 (br s,4), 8.4 (d,1), 7.6 (m,4), 7.5 (m,4), 6.9 (d,1), 4.3(q,2), 1.3 (t,3) ppm;

[0567] 3,3′-(3,5-difluoro-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.55 (br s,4), 9.4 (br s,4),8.5 (t,1), 7.7 (m,4), 7.55 (m,4) ppm;

[0568]3,3′-(4-methylaminocarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (br s,4), 9.2 (br s,4),8.85 (m,1), 7.5-7.7 (m,8), 7.2 (s,2), 2.9 (d,3) ppm;

[0569]3,3′-(3-methylaminocarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.6 (m,4), 9.4 (br s,4), 8.65(d,1), 8.5 (m,1), 7.7-8.0 (m,8), 7.2 (d,1), 2.85 (d,3) ppm.

[0570]3,3′-(3-dimethylaminocarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; m.p. 180-183° C.;

[0571]3,3′-(3-((aminocarbonyl)methylaminocarbonyl)-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2),9.25 (s,2), 9.05(s,4), 8.5 (d,1), 7.4-7.7 (m,11), 6.85 (d,1), 4.0 (d,2) ppm;

[0572]3-[(3,5-difluoro-6-(5-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]-benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.25 (s,2), 9.1 (s,2), 7.4-7.6(m,3), 7.2-7.4 (m,4), 3.1 (s,6), 2.4 (s,3), 2.1 (s,3) ppm;

[0573]3-[(3,5-difluoro-6-(3-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]-benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.25 (s,2), 9.1 (s,2), 7.5-7.7(m,4), 7.4 (m,1), 7.3 (m,1), 7.2 (d,1), 3.1 (s,6), 2.4 (s,3), 2.3 (s,3)ppm;

[0574]3-[(3,5-difluoro-6-((3-amidinophenyl)methylamino)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2), 9.3 (s,2), 9.15(s,2), 9.05 (s,2), 7.6 (m,4), 7.4 (m,3), 7.25 (m,1), 7.2 (d,1), 3.25(s,3), 2.3 (s,3) ppm;

[0575]3-[(3,5-difluoro-6-[(3-amidinophenyl)amino]-4-methylpyridin-2-yl)oxy]-benzamidine;trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2), 9.2 (s,4), 8.95(s,2), 7.5-7.8 (m,6), 7.25 (m,2), 2.35 (s,3) ppm;

[0576] 3,3′-(3,5-difluoro-4-methoxy-2,6-pyridinediylbis (oxy))bis(benzamidine), trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (br s,4),9.2 (br s,4), 7.6 (m,4), 7.5 (m,4), 4.3 (s,3), 2.3 (m,3) ppm;

[0577]3,3′-(3,5-difluoro-4-methyl-2,6-pyridinediylbis(methylamino))bis(benzamidine),trifluoroacetic acid salt; m.p. 115-120° C.;

[0578]3-[(6-(2-methoxy-5-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)-oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 7.5(m,3), 7.3 (d,1), 7.2 (m,2), 7.1 (d,₁), 3.75 (s,3), 2.9 (br,6), 2.4(s,3) ppm;

[0579]3-[(6-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)-oxy]benzamidine,trifluoroacetic acid salt; m.p. 200-202° C.;

[0580]3-[(6-(2-methyl-5-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)-oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.15 (s,2), 7.5(m,3), 7.45 (d,1), 7.3 (d,1), 7.1 (m,2), 2.95 (s,3), 2.75 (s,3), 2.4(s,3), 2.15 (s,3) ppm;

[0581]3-[(6-(3,5-di(diethylaminocarbonyl)phenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2), 9.05 (s,2), 7.6(m,3), 7.45 (m,1), 7.2 (s,2), 7.1 (s,1), 3.45 (br,4), 3.15 (br,4), 2.4(s,3) 1.2 (br,6), 1.05 (br,6) ppm;

[0582] 3-[(6-(2,3-dimethoxy-5-dimethylaminocarbonylphenoxy)-35-difluoro-4-methylpyridin-2-yl)oxy]benzamidine, trifluoroacetic acidsalt; NMR (DMSO-d₆) 9.25 (s,2), 9.1 (s,2), 7.95 (s,1), 7.4-7.6 (m,4),7.3 (s,1), 3.9 (s,3), 3.7 (s,3), 2.5 (s,6), 2.4 (s,3) ppm;

[0583]3-[(6-(3,5-difdimethylaminocarbonyl)phenoxy)-3,5-difluoro-4-methylpyridin-2-yl)-oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.05 (s,2), 7.55(m,4), 7.25 (s,2), 7.2 (s,1), 3.0 (s,6), 2.85 (s,6), 2.4,(s,3) ppm;

[0584]3-[(6-(2-methoxy-4-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.15 (s,2), 7.5(m,3), 7.35 (m,1), 7.15 (d,1), 7.1 (s,1), 6.9 (d,1), 3.7 (s,3), 3.05(br,3), 2.9 (br,3), 2.4 (s,3) ppm;

[0585]3,3′-(4-phenylcarbonylamino-2,6-pyridinediylbisoxy))bis(benzamidine),trifluoroacetic acid salt; m.p. 269-271° C.;

[0586]3,3′-(3-phenylaminocarbonylamino-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; m.p. 159-160° C.;

[0587]3,3′-(3-(aminocarbonymethyl)aminocarbonylamino-2,6-pyridinediylbis(oxy))-bis(benzamidine),trifluoroacetic acid salt; m.p. 129-130° C.;

[0588] 3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.5 (br,4), 9.2 (br,4), 7.3-7.7(m,9), 6.8 (d,1) ppm;

[0589]3,3′-[3-methylsulfonylamino-2,6-pyridinediylbisioxy)]bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.6 (s,1), 9.4 (m,8), 8.4(d,1), 7.95 (d,1), 7.5-7.7 (m,8), 6.9 (d,1), 3.1 (s,3) ppm;

[0590]3,3′-[3-methylcarbonylamino-2,6-pyridinediylbis(oxy)]bis(benzamidine),2-trifluoroacetic acid salt; NMR (DMSO-d₆) 9.8 (s,1), 9.3 (m,4), 9.25(m,4), 8.4 (d,1), 7.4-7.7 (m,8), 6.9 (d,1), 2.15 (s,3) ppm;

[0591] 3-[1(6-(3-aminophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2),9.2 (s,2), 7.6 (m,3), 7.55 (m,1), 7.0 (t,1), 6.45 (d,1), 6.35 (m,2), 2.4(s,3) ppm;

[0592] 3-[(3,5-difluoro-6-[3-[2-(1H-imidazol-1-yl)-1-oxoethyl]phenoxy]-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (s,2), 9.3 (s,2), 9.0(s,1), 7.4-7.9 (m,10), 6.0 (s,2), 2.4 (s,3) ppm;

[0593]3-[(6-(3-(2-(dimethylaminocarbonyl)ethyl)phenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.25 (s,2), 7.6(m,4), 7.2 (t,1), 7.0 (m,2), 6.9 (d,1), 2.9 (s,3), 2.8 (s,3 ), 2.75(t,2), 2.5 (m,2), 2.4 (s,3) ppm;

[0594]3-[(3,5-difluoro-6-[3-(hydroxymethyl)phenoxy]-4-methylpyridin-2-yl)oxy]-benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (br,4), 7.6 (m,4), 7.25(t,1), 7.1 (d,1), 7.05 (m,1), 7.0 (d,1), 4.45 (s,2), 2.4 (s,3) ppm;

[0595]3-[(6-(3-(dimethylaminocarbonyl)methylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,4), 7.6 (m,3), 7.55(m,1), 7.2 (t,1), 7.0 (m,2), 3.6 (s,2), 2.95 (s,3), 2.8 (s,3), 2.4 (s,3)ppm;

[0596]3-[(6-(3-(aminocarbonyl)methylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; m.p. 189-192° C.;

[0597]3-[(6-[3-(aminomethyl)phenoxy]-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (br,4), 8.2 (br,3), 7.6(m,3), 7.55 (m,1), 7.35 (t,1), 7.2 (m,2), 7.15 (d,1), 4.0 (m,2), 2.4(s,3) ppm;

[0598]3-[(3,5-difluoro-4-methyl-6-13-(prop-2-oxymethyl)phenoxylpyridin-2-yl)oxy]-benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 7.6(m,4), 7.2 (t,1), 6.65 (m,3), 4.55 (m,1), 2.4 (s,3), 1.15 (m,6) ppm;

[0599] 4,4′-[1,3-phenylenebis(oxy)]bis(benzamidine), trifluoroaceticacid salt; NMR (DMSO-d₆) 9.4 (br,4), 9.2 (br,4), 7.96 (d,4), 7.6 (t,1),7.3 (d,4), 7.05 (dd,2), 6.97 (m,₁) ppm;

[0600] 3,3′-[4-nitro-1,3-phenylenebis(oxy)]bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (s,4), 9.2 (m,4), 8.25(d,1), 7.6 (m,8), 7.0 (dd,1), 6.9 (m,1) ppm;

[0601]3-[(6-(3-methoxy-5-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)-oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 7.6(m,4), 6.8 (s,1), 6.7 (d,2), 3.7 (s,3), 3.0 (s,3), 2.8 (s,3), 2.4 (s,3)ppm;

[0602] 4-methoxy-3-[(6-(3-methoxy-5-di methylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.1 (s,2), 9.0 (s,2), 7.8(d,1), 7.7 (s,1), 7.2 (d,1), 6.7 (s,1), 6.6 (s,1), 6.5 (s,1), 3.8 (s,3),3.7 (s,3), 2.9 (s,3), 2.7 (s,3), 2.4 (s,3) ppm;

[0603]4-methoxy-3-[(6-(3-(imidazol-1-yl)phenoxy)-4-ethoxycarbonylpyridin-2-yl)oxy]-benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.1 (s,2), 8.9 (s,2), 8.0(s,1), 7.6 (m,7), 7.2 (m,4), 4.4 (q,2), 3.7 (s,3), 1.3 (t,3) ppm;

[0604]4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt, NMR (CDCl₃) 9.10 (s,2), 8.94 (s,2), 7.71(d,1), 7.66 (s,1), 7.32 (t,1), 7.25 (d,1), 7.09 (d,1), 7.01 (d,1), 6.95(s,1), 3.77 (s,3), 2.95 (s,3), 2.75 (s,3), 2.37 (s,3);

[0605]4-amino-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl) oxy]-benzamidine, trifluoroacetic acid salt; NMR (CDCl₃)8.8 (s,4),7.71 (d,1), 7.5 (d,1), 7.4 (s,1), 7.3 (t,1), 7.1-7.2 (m,2),7.1 (s,1), 6.6 (d,1), 6.2 (s,2), 3.0 (s,3), 2.8 (s,3), 2.4 (s,3) ppm;

[0606]4-amino-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-(2,2,2-trifluoroethoxy)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 8.7 (s,2), 8.5 (s,2), 7.4-7.5(m,2), 7.3 (t,1), 7.1-7.2 (m,3), 6.7 (d,1), 6.2 (br s,2), 5.2 (q,2), 3.0(s,3), 2.8 (s,3) ppm;

[0607]4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-(2,2,2-trifluoro-ethoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0608] 3,3′-[2,6-pyrazinediylbis(oxy)]bis(benzamidine), trifluoroaceticacid salt; NMR (DMSO-d₆) 9.4 (s,8), 8.4 (s,2), 7.6 (m,8) ppm;

[0609] 3,3′-[2,6-pyrimidinediylbis(oxy)]bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (m,8), 8.6 (d,1), 7.7(m,8), 7.05 (d,1) ppm;

[0610]4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-2-methoxypyridin-4-yl)-oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.3 (s,1), 9.1 (m,2), 8.8(s,2), 7.6 (m,2), 7.5 (t,1), 7.2 (m,3), 7.05 (d,1), 3.8 (s,3), 3.0(s,3), 2.9 (s,3) ppm;

[0611]4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)-(aminocarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0612]4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)-(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0613]4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(methyl)-(phenyl)aminocarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0614]4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0615]3-[(6-(3-dimethylaminocarbonylphenoxy)-4-dimethylaminocarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.31 (s,2), 9.24 (s,2), 7.35(m,8), 6.81 (s,1), 6.78 (s,1), 2.95 (m,12) ppm;

[0616]3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonyl-2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0617]3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonyl-2-(morpholin-4-ylmethyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

[0618] 3-[(3-(3-amidinophenoxy)phen-1-yl]oxy]benzamidine,trifluoroacetic acid salt.

EXAMPLE 23-[(6-(3-Amidinophenoxy)-4-carboxypyridin-2-yl)oxy]benzamidine,Dihydrochloride

[0619] 2,6-Bis(3-amidinophenoxy)pyridine-4-carboxamide (5 g, 11 mmol)was dissolved in 5M HCl and heated. The solid that precipitated oncooling was collected by filtration to give3-1(6-(3-amidinophenoxy)-4-carboxypyridin-2-yl)oxy]benzamidine,dihydrochloride; NMR (DMSO-d₆) 9.4 (br s,4), 9.2 (br s,4), 7.4 (m,4),7.3 (m,4), 7.2 (s,2) ppm.

EXAMPLE 33-[(3,5-Difluoro-4-methyl-6-[(pyridin-3-yl)oxylpyridin-2-yl)oxy]benzamidine,Acetic Acid Salt

[0620] A. In a manner similar to Example 1 above,3-[(3,5-difluoro-4-methyl-6-[(pyridin-3-yl)oxylpyridin-2-y]oxy]benzonitrilewas reacted with HCl and ammonia (g). The solvent was removed in vacuoand the material was partitioned with methylene chloride and 2N aqueouspotassium hydroxide. The organic layer was separated, acetic acid added,and the solvent was removed in vacuo. The residue was triturated withether and the resulting solid was filtered to give3-[(3,5-difluoro-4-methyl-6-l(pyridin-3-yl)-oxylpyridin-2-yl)-oxy]benzamidine,acetic acid salt; m.p. 213-214° C.

[0621] B. In a similar manner, the following compounds were made:

[0622] 3-[(3,5-difluoro-4-methyl-6-phenoxypyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 122-123° C.;

[0623]3-[(3,5-difluoro-6-(4-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 106-107° C.;

[0624]3-[(3,5-difluoro-6-[3-(1H-imidazol-1-yl)phenoxy]-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.9 (br,4), 8.3 (s,1), 7.8 (s,1), 7.65(m,6), 7.3 (t,1), 7.15 (m,2), 2.4 (s,3) ppm;

[0625]3-[(3,5-difluoro-4-methyl-6-(3-nitrophenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.1 (br,4), 8.05 (m,2), 7.7 (m,2), 7.6(m,2), 7.5 (m,2), 2.45 (s,3) 1.8 (s,3) ppm;

[0626]3-[(3,5-difluoro-4-methyl-6-[3-[(methylsulfonyl)amino]phenoxylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10 (br,4), 7.5 (m,3), 7.4 (d,1), 7.15(t,1), 6.85 (d,1), 6.8 (t,1), 6.66 (dd,1), 2.83 (s,3), 2.36 (s,3) 1.74(s,3) ppm;

[0627]3-[(3,5-difluoro-6-(3-methylcarbonylaminophenoxy)-4-methylpyridin-2-yl)oxy]-benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 10.1 (s,1), 7.4-7.7 (m,5),7.25 (m,2), 6.8 (m,1), 2.4 (s,3), 2.1 (s,3), 1.8 (s,3) ppm;

[0628]3-[(3,5-difluoro-6-(4-dimethylaminomethylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 103-105° C.;

[0629] 3-[(3,5-difluoro-4-methyl-6-(3-(morpholin-4-yl)phenoxy)pyridin-2-yl) oxy]benzamidine, acetic acid salt; m.p. 194-196° C.;

[0630]3-[(3,5-difluoro-4-methyl-6-(3-(1-pyrrolidinoyl)phenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 162-164° C.;

[0631] 3-[(3,5-difluoro-4-methyl-6-(3-(4-morpholinoyl) phenoxy)pyridin-2-yl)oxy]benzamidine, acetic acid salt; m.p. 123-126° C.;

[0632]3-[(3,5-difluoro-4-methyl-6-(3-dimethylaminocarbonylphenoxy)pyridin-2-yl)oxy]-benzamidine,acetic acid salt; m.p. 198-200° C.;

[0633] 3-[(3,5-difluoro-4-methyl-6-(3-(carboxy)(hydroxy)methylphenoxy)pyridin-2-yl)oxy]-benzamidine, acetic acid salt;NMR (DMSO-d₆) 10 (br,4), 7.4-7.7 (m,6), 7.25 (m,3), 7.15 (m,1), 7.05(m,1), 4.82 (s,1), 2.4 (s,3), 1.8 (s,3) ppm;

[0634]3-1(3,5-difluoro-4-methyl-6-[3-(1-oxoethyl)]phenoxy]pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.2 (br,4), 7.75 (m,1), 7.65 (m,1),7.4-7.6 (m,6), 2.5 (s,3), 2.41 (s,3), 1.75 (s,3) ppm;

[0635]3-[(3,5-difluoro-4-methyl-6-13-(2-methyl-1-oxopropyl)]phenoxy]pyridin-2-yl)oxy]-benzamidine,acetic acid salt; NMR (CDCl₃) 10.2 (br,4), 7.7 (m,1), 7.2-7.6 (m,7),3.45 (m,1), 2.39 (s,3), 1.88 (s,3), 1.14 (m,6) ppm;

[0636] 3-l (3,5-difluoro-4-methyl-6-(3-(dimethylaminocarbonyl)(hydroxy)methylphenoxy)-pyridin-2-yl)oxy]benzamidine, acetic acid salt;NMR (DMSO-d₆) 10 (br,4), 7.55 (m,3), 7.4 (m,1), 7.3 (t,1), 7.1 (m,3),5.35 (s,1), 2.82 (s,6), 2.40 (s,3), 1.78 (s,3) ppm;

[0637]3-(3,5-difluoro-4-methyl-6-(3-(dimethylaminocarbonyl)(methoxy)methylphenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10 (br,4), 7.5 (m,4), 7.4 (m,1), 7.3(m,2), 7.15 (d,1), 7.05 (m,2), 4.5 (s,1), 3.3 (s,3), 2.4 (s,3), 1.78(s,3) ppm; and

[0638] 4-methoxy-3-[(3,5-difluoro-4-(ethoxycarbonylmethyl)(methyl)amino-6-(3-dimethyl-aminocarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine,acetic acid salt.

EXAMPLE 43-1(3,5-Difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy1-benzamidine,Acetic Acid Salt

[0639] A.T8-[(3,5-difluoro-6-[3-dimethylaminophenoxy]-4-methylpyridin-2-yl)-oxy]benzonitrile(1.4 g, 3.7 mmol) dissolved in ethanol (100 mL) and cooled to -10° C.was bubbled hydrochloric acid (g) until saturated. The mixture wasallowed to warm to ambient temperature and the solvent was removed invacuo. The residue was dissolved in ethanol (50 mL) and heated at refluxwhile ammonia (g) was bubbled through the reaction mixture for 2 hours.The solvent was removed in vacuo and the residue was partitioned with 2N aqueous potassium hydroxide and methylene chloride. The organic layerwas separated and dried (MgSO₄). Acetic acid (1 mL) was added and thesolvent was removed in vacuo. Crystallization fromether gave3-[(3,5-difluoro-6-(3-dimethyl-aminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 176-179° C.

[0640] B. In a similar manner, the following compounds were made:

[0641]3-[(3,5-difluoro-6-(3-(2-(dimethylamino)ethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 214-216° C.;

[0642]3-[(3,5-difluoro-6-(3-aminocarbonylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,hydrochloride; NMR (DMSO-d₆) 9.4 (s,2), 9.25 (s,2), 9.1 (s,1), 7.6(m,2), 7.55 (m,2), 7.4 (s,1), 7.2 (t,1), 7.05 (d,1), 6.6 (d,1), 6.1(s,2), 2.4 (s,3), 2.1 (s,3), 1.8 (s,3) ppm;

[0643]3-[(3,5-difluoro-6-(3-ethoxycarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 198-199° C.;

[0644]3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 160-163° C.;

[0645]3-[(3,5-difluoro-6-[3-(ethylamino)phenoxy]-4-methylpyridin-2-yl)oxy]-benzamidine,acetic acid salt; m.p. 193-196° C.;

[0646]3-[(6-(3-diethylaminophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 196-197° C.;

[0647]3-[(3,5-difluoro-4-methyl-6-[3-(phenylamino)phenoxylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.0 (br,4), 8.4 (s,1), 7.4-7.7 (m,4),7.3 (t,2), 7.2 (t,1), 7.1 (d,2), 6.9 (m,2), 6.8 (s,1), 6.5 (d,1), 2.4(s,3), 1.8 (s,3) ppm;

[0648]3-[(3,5-difluoro-6-(3-methylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 8.5 (s,1), 7.6 (d,1), 7.55(m,3), 7.4 (m,3), 2.8 (d,3), 2.4 (s,3), 1.75 (s,3) ppm;

[0649] 3-l(3,5-difluoro-6-(3-(4-methylpiperazin-1-oyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 7.6 (m,3), 7.45 (m,2), 7.25(m,1), 7.1 (m,2), 3.6 (br,2), 3.2 (br,2), 2.4 (s,3), 2.35 (br,2), 2.2(br,2), 2.2 (s,3), 1.8 (s,3) ppm;

[0650]3-[(3,5-difluoro-6-(3-(piperidin-1-oyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 7.6 (m,3), 7.45 (m,2), 7.2(d,1), 7.15 (m,2), 3.6 (br,2), 3.2 (br,2), 2.4 (s,3), 1.8 (s,3) 1.3-1.6(m,6) ppm;

[0651] 3-[(3,5-difluoro-6-(3-(methyl)(benzyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 167-169° C.;

[0652] 3-[(3,5-difluoro-6-(3-(methyl)(2-pyridin-1-ylethyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 145-150° C.;

[0653] 3-[(3,5-difluoro-6-(3-(methyl)(ethyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.2 (br,4), 8.5 (m,1), 7.1-7.7 (m,8),3.4 (br,1), 3.05 (br,1), 1.8 (m,3), 2.4 (s,3), 1.75 (s,3) 1.1 (m,1.5),1.0 (m,1.5) ppm;

[0654]3-[(3,5-difluoro-6-(3-diethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 7.5 (m,3), 7.2 (m,2), 7.2(d,1), 7.1 (m,2), 3.4 (br,2), 3.05 (br,2), 2.4 (s,3), 1.8 (s,3) 1.15(br,3), 1.0 (br,3) ppm;

[0655]3-[(3,5-difluoro-6-(3-(carboxyethyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,ethyl ester, acetic acid salt;

[0656]3-[(6-(3-chlorophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 200-202° C.;

[0657] 3-[(3,5-difluoro-4-methyl-6-(3-trifluoromethylphenoxy)pyridin-2-yl) oxy]benzamidine, acetic acid salt; m.p. 192-193° C.;

[0658]3-[(3,5-difluoro-6-(3-methoxyphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 182-185° C.;

[0659]3-[(3,5-difluoro-6-(3-fluorophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 208-209° C.;

[0660]3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-4-methylbenzamidine, acetic acid salt; m.p. 192-193° C.;

[0661]3-[(3,5-difluoro-4-methyl-6-[3-[(phenyl)oxomethyl]phenoxylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 162-165° C.;

[0662] 3-[(3,5-difluoro-6-(3-hydroxyphenoxy)-4-methylpyridin-2-yl)oxylbenzamidine, acetic acid salt; m.p. 114-117° C.;

[0663]5-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-2-methoxy-benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.8 (br,4), 7.75 (d,1), 7.7 (s,1), 7.3(d,1), 7.05 (t,1), 6.45 (d,1), 6.3 (s,1), 6.15 (d,1), 3.8 (s,3), 2.85(s,6), 2.4 (s,3), 1.8 (s,3) ppm;

[0664] 3-[(6-(3-ethoxycarbonylmethylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-benzamidine, acetic acidsalt; NMR (DMSO-d₆) 10.0 (br,4), 7.55 (m,3), 7.45 (m,1), 7.25 (m,1),7.05 (m,3), 4.05 (q,2), 3.65 (s,2), 2.4 (s,3), 1.8 (s,3), 1.2 (t,3) ppm;

[0665]3-[(6-(-ethoxycarbonylmethylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine;

[0666]3-[(6-(3-(2-(ethoxycarbony)ethyl)phenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionicacid, ethyl ester, acetic acid salt; NMR (DMSO-d₆) 10.2 (br,4), 7.55(m,3), 7.45 (m,1), 7.25 (t,1), 7.0 (m,3), 4.05 (q,4), 2.8 (t,2), 2.6(m,2), 2.4 (s,3), 1.8 (s,3), 1.2 (t,3) ppm;

[0667]3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-2,6-dimethoxy-benzamidine,acetic acid salt; m.p. 109-111° C.;

[0668]3-[(3,5-difluoro-6-(3-(2-hydroxyethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 179-182° C.;

[0669]4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.6 (br,4), 7.7 (d,1), 7.6 (s,1), 7.3(t,1), 7.2 (d,1), 7.05 (d,1), 7.0 (d,1), 6.9 (s,1), 3.8 (s,3), 3.1(s,6), 2.95 (s,3), 2.8 (s,3), 1.75 (s,3) ppm;

[0670] 4-methoxy-3-1(3,5-d if Iuoro-6-(3-dimethyl aminocarbonylphenoxy)-4-(4-ethoxycarbonyl-piperidin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.0 (br,4), 7.65 (m,2), 7.3 (m,1), 7.2(m,1), 7.0 (m,3), 4.1 (q,2), 3.8 (s,3), 3.7 (m,2), 3.3 (m,2), 3.0 (s,3),2.8 (s,3), 2.7 (m,1), 2.0 (m,2), 1.75 (s,3), 1.25 (t,3) ppm; and

[0671]4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-ethoxycarbonyl-piperidin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.2 (br,4), 7.8 (d,1), 7.7 (s,1), 7.3(m,2), 7.0 (m,3), 4.1 (q,2), 3.8.(s,3), 3.7 (m,1), 3.4 (m,5), 3.0 (s,3),2.8 (s,3), 2.7 (m,1), 2.0 (s,3), 1.8 (m,4), 1.1 (t,3) ppm.

EXAMPLE 54-Amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-benzamidine,Acetic Acid Salt

[0672] A. In a manner similar to Example 1 above,4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzenecarbonitrile was reacted with hydrogen chloride and ammonia.The resulting residue was purified by HPLC on a C18 Dynamax column witha 20-80% acetonitrile in water gradient with 0.1% trifluoroacetic acidand the material was partitioned with ethyl acetate and aqueous sodiumbicarbonate. The organic layer was separated, dried (MgSO₄), and thesolvent was removed in vacuo. The residue was dissolved in water,acidified with acetic acid, and the solvent removed to give4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)-oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10 (br,4), 7.45 (m,2), 7.03 (t,1), 6.79(d,1), 6.44 (dd,1), 6.33 (t,1), 6.29 (d,1), 6.16 (s,1), 3.36 (s,2), 2.84(s,6), 2.38 (s,3), 1.76 (s,3) ppm.

[0673] B. In a similar manner, the following compound was made:

[0674]4-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)aminol-3-hydroxy-benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.94 (s,1), 9.01 (s,2), 8.71 (s,2),7.86 (d,1), 7.65 (s,1), 7.26 (t,1), 7.19 (d,1), 6.89 (dd,1), 6.64(dd,1), 6.54 (m,1), 6.44 (dd,1), 3.4 (s,1), 2.90 (s,6), 2.32 (s,3) ppm.

EXAMPLE 64-Hydroxy-3-1(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-benzamidine,Trifluoroacetic Acid Salt

[0675] A. To5-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-4-methoxy]benzamidine,trifluoroacetic acid salt (0.80 g, 1.9 mmol) in methylene chloride (70mL) at −78° C. was added boron tribromide (1M in methylene chloride, 9mL, 9 mmol). The reaction was warmed to ambient temperature. Afterstirring for 16 hours, the reaction was concentrated and purified byHPLC as described above in Example 5 to give4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.06 (s,2), 8.88 (s,2), 7.67(m,1), 7.62 (d,1), 7.1 (d,1), 7.04 (t,1), 6.45 (d,1), 6.32 (m,1), 6.23(d,1), 2.85 (s,6), 2.4 (s,3) ppm.

[0676] B. In a similar manner, the following compounds were made:

[0677]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-dimethylamino-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.0 (s,2), 8.8(s,2), 7.6 (m,2), 7.3 (t,1), 7.0 (m,4), 3.1 (s,6), 2.95 (s,3), 2.8 (s,3)ppm;

[0678] 4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonyl-piperidin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.0 (s,2), 8.9 (s,2), 7.55(m,2), 7.3 (t,1), 7.0 (m,4), 4.1 (q,2), 3.6 (m,2), 3.3 (m,2), 3.0 (s,3),2.8 (s,3), 2.6 (m,1), 2.0 (m,2), 1.7(s,2), 1.15 (t,3) ppm;

[0679]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-ethoxycarbonyl-piperidin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.2 (br,4), 7.6 (m,2), 7.3 (t,1), 7.0(m,4), 4.1 (q,2), 3.8 (s,3), 3.2-3.7 (m,4), 3.0 (s,3), 2.8 (s,3), 2.7(m,1), 2.0 (s,3), 1.8 (m,4), 1.1 (t,3) ppm;

[0680]4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.1 (s,2), 8.85(s,2), 7.9 (t,1), 7.6 (m,2), 7.4 (t,1), 7.15 (m,2), 7.05 (m,2), 6.75(d,1), 6.7 (d,1), 2.95(s,3), 2.8 (s,3) ppm;

[0681]4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(4-methylpiperazin-1-oyl)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 10.1 (br,1), 9.05(s,2), 8.85 (s,2), 7.6 (m,2), 7.4 (t,1), 7.2 (m,2), 7.05 (m,2), 6.8(s,1), 6.7 (s,1), 3.5 (m,8), 2.95 (s,3), 2.8 (s,3) ppm;

[0682]4-hydroxy-3-[(3,5-difluoro-6-(5-hydroxy-3-dimethylaminocarbonylphenoxy)-4-methyl-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.9 (s,1), 9.0(s,2), 8.8 (s,2), 7.6 (m,2), 7.0 (d,1), 6.5 (s,1), 6.4 (s,1), 6.3 (s,1),2.9 (s,3), 2.7 (s,3), 2.4 (s,3) ppm;

[0683]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 11.20 (bs,1), 8.98 (s,2), 8.66(s,2), 7.59 (s,1), 7.53 (d,1), 7.29 (t,₁), 7.18-6.92 (m,4), 2.96 (s,3),2.78 (s,3), 2.36 (s,3), 1.91 (s,1.5) ppm;

[0684]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,2,2-trifluoro-ethoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.1(s,1), 9.0 (s,2), 8.8(s,2), 7.6 (m,2), 7.3 (t,1), 7.0-7.1 (m,4), 5.2 (q,2), 3.0 (s,3), 2.8(s,3) ppm;

[0685]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-hydroxy-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CD₃CN) 8.7 (s,2), 7.5 (s,2), 7.3-7.4(m,4), 7.2 (dt,1), 7.1 (dd,1), 7.0 (t,1), 6.8 (d,1), 3.1 (s,3), 3.0(s,3) ppm;

[0686]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CD₃CN) 9.8 (s,2), 7.3-7.4 (m,4), 7.2(d,1), 7.1 (d,1), 7.0 (s,1), 6.8 (d,1), 5.1 (t,1), 4.8 (d,4), 3.1 (s,3),3.0 (s,3) ppm;

[0687]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-bromo-3-fluoro-prop-2-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CD₃CN) 10.8 (s,2), 7.3-7.4 (m,4), 7.2(d,1), 7.1 (d,1), 7.0 (s,1), 6.8 (d,1), 5.1 (m,1), 4.9 (d,1), 4.7 (d,1),3.8 (d,1), 3.1 (s,3), 3.0 (s,3) ppm;

[0688]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1,3-dibromoprop-2-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.1 (s,1), 9.0 (s,2), 8.8(s,2), 7.5-7.6 (m,2), 7.3 (t,1), 7.1 (m,2), 7.0 (m,2), 5.1 (t,1), 3.9(d,4), 3.0 (s,3), 2.8 (s,3) ppm;

[0689]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,hydrochloride salt; NMR (DMSO-d₆) 9.0 (s,2), 8.7 (s,2), 7.6 (m,2), 7.2(t,1), 7.0 (m,4), 4.1 (s,2), 3.2 (s,3), 2.9 (s,3), 2.8 (s,3) ppm;

[0690]4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-carboxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.12 (s,2), 9.16 (s,2), 9.03(s,2), 7.3 (m,9), 2.99 (s,3), 2.87 (s,3) ppm;

[0691]4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonyl)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.06 (s,2), 8.76(s,2), 8.3 (s,1), 7.85 (s,1), 7.3 (m,9), 2.98 (s,3), 2.86 (s,3) ppm;

[0692]4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(dimethylamino-carbonyl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.95 (s,1), 9.08 (s,2), 8.72(s,2), 7.3 (m,7), 6.72 (s,1), 6.66 (s,1), 2.95 (m,12) ppm;

[0693]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

[0694]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0695]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

[0696]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

[0697] C. In a similar manner, the following compounds are made:

[0698]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0699]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;and

[0700]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine.

EXAMPLE 74-Hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-1-yl)-pyridin-2-yl)oxy]benzamidine,Trifluoroacetic Acid Salt

[0701] A. In a manner similar to Example1,3-[(6-(5-cyano-2-(benzyloxy)phenoxy)-3,5-difluoro-4-(piperidin-1-yl)pyridin-2-yl)oxy]-N,N-dimethylbenzamidewas reacted with HCl and ammonia. The solvent was removed in vacuo. Thematerial was dissolved in methanol and Pd(C) was added. The reaction wasplaced under an atmosphere of hydrogen at 50 psi for 2 hours. Thereaction was filtered through celite and the solvent was removed invacuo. The material was partially dissolved in 0.25N aqueous potassiumhydroxide and the solid was removed by filtration. The solid waspurified by HPLC as described above in Example 5 to give4hydroxy-3-[(3,5-difluoro-6-(3-dimethyl-aminocarbonyl]phenoxy)-4-(piperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt, as the final product; NMR (DMSO-d₆) 11.0(s,1), 9.0 (s,2), 8.7 (s,2), 7.6 (m,2), 7.3 (t,1), 7.0 (m,4), 3.4 (m,4),2.95 (s,3), 2.8 (s,3), 1.65 (m,6) ppm.

[0702] B. In a similar manner, the following compounds were made:

[0703]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.2 (s,1), 10.3 (br,1), 9.0(s,4), 7.6 (m,2), 7.3 (m,2), 7.0 (m,4), 3.6 (m,8), 3.0 (s,3), 2.9 (s,3),2.8 (s,3), 1.65 (m,6) ppm;

[0704]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(ethoxy-carbonylmethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt;

[0705]4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(ethoxycarbonyl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 11.14 (s,1), 9.37-8.88 (m,8 ),7.76-7.06 (m,9), 4.35 (q,2), 1.32 (t,3) ppm;

[0706]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(morpholin-4-yl)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.0 (s,2), 8.6 (s,2), 7.5(m,2), 7.3 (t,1), 7.0 (m,4), 3.7 (m,4), 3.4 (m,4), 2.9 (s,3), 2.8 (s,3)ppm;

[0707] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(methyl)(phenyl)amino-carbonylpyridin-2-yl)oxy]benzamidine;

[0708]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methoxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0709]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxy-carbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0710]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0711]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0712]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxy-carbonylphenoxy]pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0713]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(prop-2-oxycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidinetrifluoroacetic acidsalt;

[0714]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(ethoxycarbonyl)ethyl-piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0715] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(ethoxycarbonyl)methyl-piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine, trifluoroaceticacid salt;

[0716]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonyl-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0717]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0718]4-hydroxy-3-[(3,5-difluoro-6-(3-guanidinophenoxy)-4-(1-(ethoxycarbonyl)methylpiperidin-4-yl-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0719]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-(ethoxy-carbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0720]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(ethoxycarbonylmethyl)-piperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0721]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-ethoxycarbonyl-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.35 (s,1), 10.41 (s,1), 9.03(d,4), 7.35-7.62 (m,6), 7.0 (d,1), 5.57 (s,1), 4.64 (dd,1), 4.22 (q,2),4.05 (dd,2), 3.95 (dd,1), 3.78 (d,1), 3.65 (d,1), 2.96 (s,3), 2.75(m,1), 2.55 (m,1), 1.23 (t,3) ppm;

[0722]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0723]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-methoxycarbonyl-methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0724]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0725]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonyl-methylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0726]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-aminocarbonylmethyl-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0727]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-(3,5-di(ethoxycarbonyl)phenoxy)pyridin-4-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0728]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0729]4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-benzylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0730]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-ethoxy-carbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0731]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0732]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0733]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0734] 4-hydroxy-3-[(3,5-difluoro-6-(3-(dimethylaminomethyl)phenoxy)-4-(2-methoxy-4-ethoxy-carbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0735]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-ethoxy-carbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0736]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-ethoxy-carbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0737]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0738]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0739]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0740]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0741]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0742]4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(2-methoxy-4-ethoxycarbonyl-phenoxy)pyridin-2-yl)oxy)benzamidine,trifluoroacetic acid salt;

[0743] 4-hydroxy-3-[(6-(3-amidinophenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0744]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0745]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethyl-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

[0746]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-ethoxy-carbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

[0747]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0748]4-hydroxy-3-[(3,5-ditluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0749]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0750]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methoxy-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0751]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-propoxy-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0752]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonyl-methylpiperazinyl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0753]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)-(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0754]4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(tetrahydrofuran-3-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0755]4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0756]4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-3-yloxy)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

[0757]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0758]4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0759]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0760]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-methoxy-pyridin-4-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0761]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-4-yl)oxy]benzamidine, trifluoroacetic acid salt;

[0762]4-hydroxy-3-[3-(3-dimethylaminocarbonylphenoxy)-4-(methylamino)carbonyl-aminophen-1-yloxy]benzamidine,trifluoroacetic acid salt;

[0763]4-hydroxy-3-[(3-(3-dimethylaminocarbonylphenoxy)-2,4,6-trichloro-5-fluoro-phen-1-yl)oxy]-benzamidine,trifluoroacetic acid salt;

[0764]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0765]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzyl-piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0766]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)-(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0767]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzyl-piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamnidine;

[0768]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(1-(methoxy-carbonyl)ethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0769]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0770]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(1-(hydroxymethyl)ethoxycarbonyl)phenoxy) pyridin-2-yl)oxy]benzamidine,trifluoroaceticacid salt;

[0771]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(prop-2-oxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0772]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(2-(methoxy)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0773]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-n-butoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0774]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-((2-(2-hydroxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0775] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-((2-(2-methoxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroaceticacid salt;

[0776]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-(aminocarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0777]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0778]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0779]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(2-chloro-1-methylethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

[0780]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)pphenoxy)-4-(3-(2-(ethoxycarbonyl)ethenyl) phenoxy)pyridin-2-yl) oxy]benzamidine, trifluoroacetic acidsalt;

[0781]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[0782]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxy-carbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

[0783]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-ethoxycarbonyl-phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

[0784] C. In a similar manner, the following compounds are made:

[0785]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-methyl-1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0786]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(1-methyl-1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0787]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(1-methyl-1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0788]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phehoxy)-4-(4-(1-methyl-1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0789]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0790]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-aminocarbonyl-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0791]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(5-aminocarbonyl-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0792] -b4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-aminocarbonyl-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0793]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(5-aminocarbonyl-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0794] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-methylcarbonyl-piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0795]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-methylcarbonyl-piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0796] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-methylcarbonyl-piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0797]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-methylcarbonyl-piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0798]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((ethoxycarbonyl)-methoxy)pyridin-2-yl)oxy]benzamidine;

[0799]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((ethoxycarbonyl)-methoxy)pyridin-2-yl)oxy]benzamidine;

[0800] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((ethoxycarbonyl)-methoxy)pyridin-2-yl)oxy]benzamidine;

[0801]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((ethoxycarbonyl)-methoxy)pyridin-2-yl)oxy]benzamidine;

[0802] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-ethyl-5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0803]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethyl-5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0804]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-ethyl-5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0805] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-ethyl-5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0806]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(tetrazol-5-ylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0807]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(tetrazol-5-ylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0808]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(tetrazol-5-ylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0809]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(tetrazol-5-ylmethyl)piperidin-4-yloxy) pyridin-2-yl)oxy]benzamidine;

[0810]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0811]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0812]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0813]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0814]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0815]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0816]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-chloro-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0817]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-chloro-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0818]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0819]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0820]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-chloro-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0821]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-chloro-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0822]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-ethoxycarbonyl-1-methylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0823]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonyl-1-methylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0824]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-ethoxycarbonyl-1-methylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0825]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-ethoxycarbonyl-1-methylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0826]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2-ethoxycarbonylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0827]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-ethoxycarbonylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0828]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((2-ethoxycarbonylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0829]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-ethoxycarbonylethyl)piperidin-4-yloxy) pyridin-2-yl)oxy]benzamidine;

[0830]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0831]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0832]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0833]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(morpholin-4-yl)-pyridin-2-yl)oxy]benzamidine;

[0834]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(morpholin-4-yl)-pyridin-2-yl)oxy]benzamidine;

[0835]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(morpholin-4-yl)-pyridin-2-yl)oxy]benzamidine;

[0836]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(piperidin-1-yl)-pyridin-2-yl)oxy]benzamidine;

[0837]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(piperidin-1-yl)-pyridin-2-yl)oxy]benzamidine;

[0838]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(piperidin-1-yl)-pyridin-2-yl)oxy]benzamidine;

[0839]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-methoxypyridin-2-yl)oxy]benzamidine;

[0840]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)-4-methoxypyridin-2-yl)oxy]benzamidine;

[0841]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-methoxypyridin-2-yl)oxy]benzamidine;

[0842]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(prop-2-oxycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)-oxy]benzamidine;

[0843]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(prop-2-oxyycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)-oxy]benzamidine;

[0844]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(prop-2-oxyarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0845]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(ethoxycarbonyl)ethylpiperidin-4-yloxy)pyridin-2-yl) oxy]benzamidine;

[0846]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(ethoxycarbonylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0847]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(l-(ethoxycarbonyl)ethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0848] 4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonylmethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0849]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-ethoxycarbonylmethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[0850]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0851]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0852]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(1-(ethoxycarbonyl)-ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0853]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-ethoxycarbonylmethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0854]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-ethoxycarbonylmethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0855]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0856]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0857]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0858]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0859]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0860]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-ethoxycarbonyl-methylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0861]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0862]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-ethoxycarbonyl-methylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0863]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0864]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-ethoxycarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine;

[0865]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0866]4-hydroxy-3-[(3,5-dichloro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-benzylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0867]4-hydroxy-3-[(3,5-dichloro-6-(3-(guanidino)phenoxy)-4-(1-benzylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0868]4-hydroxy-3-[(3,5-dichloro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-benzylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[0869]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0870]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0871]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0872]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0873]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0874]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0875]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0876]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0877]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0878]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0879]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0880]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0881]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0882]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0883]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-ethoxycarbonyl-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0884] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-ethoxycarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine;

[0885]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-ethoxycarbonyl-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0886]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0887]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0888]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0889]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl) oxy]benzamidine;

[0890]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0891]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0892]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0893]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0894] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-chloro-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0895]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-chloro-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0896]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethyl-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0897]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethyl-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0898]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethyl-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0899]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-ethoxy-carbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0900]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-ethoxy-carbonylethyl)phenoxypyridin-2-yl)oxy]benzamidine;

[0901]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-ethoxy-carbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0902]4-hydroxy-3-[(3,5-diflIuoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0903]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0904] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methyli midazol-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0905]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0906]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0907] 4-hydroxy-3-[(3,5-difl u oro-6-(3-(1-methyl i m idazol-2-yl)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0908]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0909]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0910] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methyli m idazol-2-yl)phenoxy)-4-(2-methoxy-phenoxy)pyridin-2-yl)oxy]benzamidine;

[0911]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-propoxy-pyridin-2-yl)oxy]benzamidine;

[0912]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidinophenoxy)-4-propoxy-pyridin-2-yl)oxy]benzamidine;

[0913]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-propoxy-pyridin-2-yl)oxy]benzamidine;

[0914]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((methyl)-(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine;

[0915]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)-4-((methyl)-(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine;

[0916]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((methyl)-(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine;

[0917]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;

[0918]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;

[0919]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;

[0920]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-pyridin-2-yl)oxy]benzamidine;

[0921]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-pyridin-2-yl)oxy]benzamidine;

[0922]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-pyridin-2-yl)oxy]benzamidine;

[0923]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylIphenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0924] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0925]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0926]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-benzyl-piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0927]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-benzyl-piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0928]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-benzyl-piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0929]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((piperidin-4-yl)-(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0930]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((piperidin-4-yl)-(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0931]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((piperidin-4-yl)-(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0932]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-benzyl-piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0933]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-benzyl-piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0934] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-benzyl-piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[0935]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-(1-(methoxy-carbonyl)ethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0936]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-(1-(methoxy-carbonyl)ethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0937]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-(1-(methoxy-carbonyl)ethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[0938]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0939]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0940]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[0941]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-(1-(hydroxymethyl)ethoxycarbonyl)phenoxy)pyridin-2-yl) oxy]benzamidine;

[0942]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(2-(hydroxymethyl)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0943]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(1-(hydroxymethyl)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0944]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-(prop-2-oxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0945]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(prop-2-oxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0946]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(prop-2-oxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0947]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-(2-(methoxy)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0948]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(2-(methoxy)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0949]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(2-(methoxy)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0950]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-n-butoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0951]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-n-butoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0952]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-n-butoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0953]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-((2-(2-hydroxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0954]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-((2-(2-hydroxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0955]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-((2-(2-hydroxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0956] 4-hydroxy-3-[(3,5-difluoro-6-(3-di methyl aminocarbonylphenoxy)-4-(2-methoxy-4-((2-(2-methoxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0957]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-((2-(2-methoxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine9;

[0958]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-((2-(2-methoxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0959]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-(aminocarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0960]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-(aminocarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0961]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-(aminocarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0962]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0963]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0964]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0965]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0966]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0967]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0968]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-(2-chloro-1-methylethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0969]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(2-chloro-1-methylethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0970]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(2-chloro-1-methylethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0971]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0972]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0973]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0974]4-hydroxy-3-1(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0975]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(2-(ethoxycarbonyl)-ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0976]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0977]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0978]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0979]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0980]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[0981] 4-hydroxy-3-[(3,5-difluoro-6-(3-(l1-methylim id azolin-2-yl)phenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0982]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0983]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[0984]4-hydroxy-3-[(3,5-difluoro-6-(3-(3-methylimidazolin-2-yl)phenoxy)-4-dimethylamino-pyridin-2-yl)oxy]benzamidine;

[0985]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-dimethylamino-pyridin-2-yl)oxy]benzamidine;

[0986]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-dimethylamtidno-pyridin-2-yl)oxy]benzamidine;

[0987]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;

[0988]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;

[0989]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;

[0990]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,2,2-trifluoro-ethoxy)pyridin-2-yl)oxy]benzamidine;

[0991] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-.(2,2,2-trifluoro-ethoxy)pyridin-2-yl)oxy]benzamidine;

[0992]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,2,2-trifluoro-ethoxy)pyridin-2-yl)oxy]benzamidine;

[0993]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;

[0994]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;and

[0995]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine.

EXAMPLE 84-Hydroxy-3-[(3,5-difluoro-6-(3-(imidazol-1-yl)phenoxy)-4-(carboxy)-pyridin-2-yl)oxy]benzamidine,Trifluoroacetic Acid Salt

[0996] A. In a manner similar to Example 6,2-(5-amidino-2-hydroxyphenoxy)-6-(3-(imidazol-1-yl)phenoxy)pyridine-4-carboxylicacid, ethyl ester was reacted with boron tribromide. The resulting oilwas dissolved in 6N HCl and heated at reflux for 2 hours. Concentrationof the mixture in vacuo and purification by HPLC as described above inExample 5 gave4-hydroxy-3-[(3,5-difluoro-6-(3-(imidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)-oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d6,TFA) 9.7 (s,1), 9.0 (s,2), 8.8(s,2), 8.3 (s,1), 7.9 (s,1), 7.6 (m,5), 7.3 (m,1), 7.1 (m,2), 7.0 (m,1)ppm.

[0997] B. In a similar manner, the following compound was made:

[0998]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(carboxy)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.1 (s,2), 8.7(s,2), 7.7 (m,2), 7.2 (m,2), 7.0 (s,1), 6.8 (s,1), 6.6 (d,1), 6.4 (m,2),2.8 (s,6) ppm.

EXAMPLE 93,3′-[4-Aminocarbonyl-2,6-pyridinediylbis(oxy)]bis(benzamidine),Trifluoroacetic Acid Salt

[0999] A. In a manner similar to Example 1 above, reaction of3,3′-[4-ethoxy-carbonyl-2,6-pyridinediylbis(oxy)]bis(benzonitrile) gave3,3′-[4-aminocarbonyl-2,6-pyridinediylbis(oxy)]-bis(benzamidine), whichwas purified by HPLC as described above in Example 5 to give thetrifluoroacetic acid salt, m.p. >210° C.; NMR (DMSO-d₆) 9.3 (s,4), 9.1(s,4), 8.3 (s,1), 7.8 (s,1), 7.65 (m,4), 7.55 (m,4), 7.2 (s,2) ppm.

[1000] B. In a similar manner, the following compounds were made:

[1001] 3,3′-[3-aminocarbonyl-2,6-pyridinediylbis(oxy)]bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO) 9.45 (br s,4), 9.35 (br s,4), 8.4(d,1), 7.4-7.9 (m,10), 6.95 (d,1) ppm; and

[1002]4-methoxy-3-[(6-(3-dimethylaminophenoxy)-4-aminocarbonylpyridin-2-yl)oxy]benzamidinehydrochloride, NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 8.3 (s,1), 7.8 (m,2),7.3 (s,1), 7.1 (m,3), 6.9 (s,1), 6.5 (d,1), 6.3 (m,2), 3.8 (s,3), 2.8(s,6) ppm.

EXAMPLE 10 2,6-bis(3-Amidinophenoxy)pyridine,3-carboxylic acid,Dihydrochloride

[1003] A. In a manner similar to Example 2 above,2,6-bis(3-amidinophenoxy)-pyridine-3-carboxylic acid, ethyl ester (0.20g, 0.31 mmol) was dissolved in 5M HCl and heated for 2 hours at 80 IC.The solvent was removed in vacuo to give2,6-bis(3-amidinophenoxy)-pyridine-3-carboxylic acid, dihydrochloride;NMR (DMSO-d₆) 9.5 (br s,4), 9.35 (br s,4), 8.45 (d,1), 7.7 (m,2), 7.6(m,2), 7.5 (m,4), 6.95 (d,1) ppm.

[1004] B. In a similar manner, the following compounds were made andpurified by HPLC as described above in Example 5:

[1005]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

[1006]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxyphenoxy)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1007]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(ethoxycarbonylmethoxy)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1008]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1009]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1010]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1011]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1012]4-hydroxy-3-1(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1013]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1014]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1015]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-carboxyethyl)-phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1016] 4-hydroxy-3-[(3,5-difluoro-6-(3-(l1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-carboxy-ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1017]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(2-carboxy-ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1018]4-hydroxy-3-[(3,5-difluoro-6-(3-(dimethylaminomethyl)phenoxy)-4-(2-methoxy-4-carboxy-phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1019]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1020]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1021]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-5-ethoxy-carbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1022]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1023]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1024]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1025]4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(2-methoxy-4-carboxy-phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1026] 4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1027]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1028]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-dimethyl-aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1029]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-dimethyl-aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1030]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxy-methylpiperidin-4-y)(methyl)amino)pyridin-2-yl)oxy]benzamidine, trifluoroaceticacidsalt; NMR(DMSO-d₆) 11.25 (s,1), 10.30 (s,1), 9.03 (br s,4), 7.58-7.55 (m, 2),7.50 (t,1), 7.38-7.31 (m,3), 7.03 (d,1), 4.10 (s,2), 4.08-3.88 (m,4),3.66 (m,2), 3.16 (m,2), 2.95 (s,6), 2.26 (m,2), 1.93(m,2) ppm;

[1031]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1032]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,hydrochloride salt; NMR (DMSO-d₆) 11.25 (s,1), 10.45 (s,1), 9.1 (d,4),7.35 (m,7), 4.18 (s,2), 4.05 (m,4), 3.2 (s,3), 2.95 (s,3) ppm;

[1033]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

[1034] C. In a similar manner, the following compounds are made:

[1035]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-methyl-1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1036]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(1-methyl-1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1037]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(1-methyl-1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1038]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(1-methyl-1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1039]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1040]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1041]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(1-(carboxy)ethyl)-piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1042]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1043]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1044]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1045]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1046]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1047]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-(carboxy)ethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1048]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-(carboxy)ethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1049]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(1-(carboxy)ethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1050]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(1-(carboxy)ethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1051]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1052]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1053]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1054]4-hydroxy-3-1(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1055]4-hydroxy-3-[(6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1056]4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1057]4-hydroxy-3-[(6-(3-(guanidino)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1058]4-hydroxy-3-[(6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1059]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(carboxymethoxy)pyridin-2-yl)oxy]benzamidine;

[1060]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(carboxymethoxy)pyridin-2-yl)oxy]benzamidine;

[1061]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(carboxymethoxy)pyridin-2-yl)oxy]benzamidine;

[1062]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(carboxymethoxy)pyridin-2-yl)oxy]benzamidine;

[1063]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1064]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1065]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1066]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1067]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1068]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1069]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1070]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1071]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1072]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1073]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[1074]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[1075]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

[1076]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1077]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1078]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1079]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1080]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1081]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[1082]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[1083]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[1084]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[1085]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;

[1086]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;

[1087]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

[1088]4-hydroxy-3-1(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

[1089]4-hydroxy-3-[(3,5-difluoro-6-(3-(9uanidino)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1090]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl) oxy]benzamidine;

[1091]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1092]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1093]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1094]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1095]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1096]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1097]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1098]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1099]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(carboxymethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[1100]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(carboxymethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[1101]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(carboxymethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[1102]4-hydroxy-3-1(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2-dimethyl-aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;and

[1103]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((2-dimethyl-aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine.

EXAMPLE 114-Hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(ethoxycarbonyl-methyl)pyrrolidin-3-yloxy)pyridin-2-yloxy]benzamidine,Trifluoroacetic Acid Salt

[1104] A. To ethanol (40 mL) was added

[1105]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethyl-aminophenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yloxy]-benzamidine(0.44 g, 0.90 mmol), ethyl bromoacetate (0.15 g, 0.9 mmol), andtriethylamine (0.11 g, 1.1 mmol). After stirring for 19 hours, thereaction mixture was concentrated and purified by HPLC as describedabove in Example 5 to give4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylamino-phenoxy)-4-(1-(ethoxycarbonylmethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)-oxy]benzamidine, trifluoroacetic acid salt.

[1106] B. In a similar manner, the following compounds were made:

[1107]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonyl-methylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1108]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxy-carbonylmethyl-piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;and

[1109]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(ethoxycarbonyl-methyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

[1110] C. In a similar manner, the following compounds are made:

[1111]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-(ethoxycarbonyl-methyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[1112]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-(ethoxycarbonyl-methyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[1113]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-(ethoxycarbonyl-methyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[1114]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-ethoxy-carbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[1115] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanid ino)phenoxy)-4-((1-ethoxy-carbonylmethylpiperidin-4-yl) (methyl)amino)pyridin-2-yl) oxy]benzamidine; and

[1116]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-ethoxy-carbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine.

EXAMPLE 123-[(3,5-Difluoro-6-(3-carboxyphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,Hydrochloride Salt

[1117] A. To3-[(3,5-difluoro-6-(3-ethoxycarbonylphenoxy)-4-methylpyridin-2-yl)-oxy]benzamidine,acetic acid salt (1.0 g, 2.0 mmol) dissolved in methanol (40 mL) wasadded 5N potassium hydroxide (20 mL). After stirring for 4 hours, thesolvent was removed in vacuo. The residue was dissolved in water (50 mL)and acidified with 12N HCl. The resulting solid was filtered and washedwith ether to give3-[(3,5-difluoro-6-(3-carboxyphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,hydrochloride salt; NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 7.7 (d,1), 7.65(s,1), 7.3-7.6 (m,6), 2.4 (s,3) ppm. If necessary the material can befurther purified by HPLC as described above in Example 5.

[1118] B. In a similar manner, the following compounds were made:

[1119]3-1(3,5-difluoro-6-(3-(2-carboxyethyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,m.p. 145-150° C.;

[1120]3-l(3,5-difluoro-6-(3-(2-carboxyethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.2 (s,2), 7.6(m,4), 7.25 (t,1), 7.0 (m,2), 6.95 (m,1), 2.8 (t,2), 2.6 (m,2), 2.4(s,3) ppm;

[1121]3-[(3,5-difluoro-6-(3-(carboxymethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2),9.2 (s,2), 7.6 (m,4),7.25 (t,1), 7.0 (m,3), 3,.4 (s,2), 2.4 (s,3) ppm;

[1122]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;NMR (DMSO-d₆) 9.75 (br,2), 8.5 (br,2), 7.5 (m,2), 7.3 (t,1), 7.0 (m,3),6.65 (d,1), 3.6 (m,2), 3.2 (m,2), 2.95 (s,3), 2.8 (s,3), 2.3 (m,1), 1.9(m,2), 1.7 (m,2) ppm;

[1123]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;NMR (DMSO-d₆) 9.75 (br,2), 8.7 (br,2), 7.5 (m,2), 7.3 (t,1), 7.0 (m,3),6.8 (d,₁), 3.2-3.68 (m,4), 2.95 (s,3), 2.8 (s,3), 2.4 (m,1), 2.0 (m,₁),1.8 (m,₁), 1.6 (m,2) ppm;

[1124]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxymethyl-piperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.1 (s,1), 9.0 (br,2), 8.9(br,2), 7.65 (m,2), 7.3 (m,1), 7.0 (m,4), 4.1 (s,2), 3.6 (m,8), 3.0(s,3), 2.8 (s,3), ppm;

[1125]4-hydroxy-3-[(6-(3-amidinophenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 11.16 (s,1), 9.38-8.95 (m,8),7.68-7.04 (m,9) ppm;

[1126] 3-l(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(N-methyl-N-carboxymethyl-amino)pyridin-2-yl)oxy]benzamidine;NMR (DMSO-d₆) 9.3 (s,2), 9.2 (s,2), 7.5 (m,4), 7.2 (t,1), 6.7 (m,2), 6.5(d,1), 4.2 (s,2), 3.2 (s,3), 2.9 (s,6) ppm;

[1127]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1128]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1129]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.30 (s,1), 10.37 (s,1), 9.00(s,2), 8.99 (s,2), 7.61 (d,1), 7.57 (dd, 1), 7.52-7.32 (m,4), 7.04(d,1), 6.55 (s,1), 4.52 (dd,1), 4.02 (dd,2), 3.88 (dd,2), 3.72 (dd,1),3.58 (d,1), 2.92 (s,3), 2.63 (dd,₁), 2.44 (dd,1);

[1130]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.29 (s,1), 10.31 (s,1), 9.05(s,2), 9.02 (s,2), 7.63-7.57 (m, 2), 7.52 (t,1), 7.42-7.37 (m,3), 7.04(d,1), 4.92 (br s,1), 4.15 (s,2), 4.09-3.92 (m,4), 3.60-3.40 (m,4), 2.95(s,3), 2.32-2.10 (m,4) ppm;

[1131]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;NM R (DMSO-d₆) 11.34 (s,1), 10.46 (s,1), 9.21 (s,2), 8.99(s,2), 7.70(s,1), 7.63 (d, 1), 7.54 (t,₁), 7.43-7.40 (m,2), 7.15 (d,1), 4.96 (brs,1), 4.12-4.09 (m,2), 3.96-3.90 (m,2), 3.40-3.20 (m,4), 2.97 (s,3),2.40-2.30 (m,2), 2.28-2.14 (m,2), 1.54 (s,6) ppm;

[1132]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1133]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

[1134]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(carboxymethyl)(methyl)-aminocarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1135]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-carboxy-methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1136]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1137]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1138]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(carboxymethyl)amino-carbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1139]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1140]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-carboxymethoxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1141]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(carboxymethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1142]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(carboxymethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1143]4-hydroxy-3-[(6-(3-(2,4-dimethylimidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1144]4-hydroxy-3-[(6-(3-(2-methylimidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1145]4-hydroxy-3-[(6-(3-(4-methylimidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidin,trifluoroacetic acid salt;

[1146]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxymethyl-piperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1147]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1148]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-(morpholin-4-ylmethyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1149]4-hydroxy-3-[(6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1150]4-hydroxy-3-[(6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1151]4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1152]3-hydroxy-4-[(6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1153]3-hydroxy-4-[(6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1154]4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(carboxymethyl)-(methyl)aminocarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1155]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxy-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1156]4-hydroxy-3-[(6-(3-dimethylaminophenoxy)-4-(4-carboxymethylpiperazin-1-oyl)pyridin-2-yl)oxy]benzamidine;and

[1157]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

[1158] C. In a similar manner, the following compounds are made:

[1159]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1160]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1161]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1162]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1163]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1164]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1165]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1166]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1167]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-carboxy-methylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

[1168]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-carboxy-methylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

[1169]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;

[1170]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1171]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1172]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1173]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1174]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

[1175]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1176]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

[1177]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1178]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1179] 4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-hlydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1180]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1181]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1182]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1183]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1184]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;

[1185]4-hydroxy-3-l(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;

[1186]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;

[1187]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

[1188]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1189]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1190]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

[1191]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[1192]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

[1193]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

EXAMPLE 133-[(3,5-Difluoro-6-(3-((phenyl)hydroxymethyl)phenoxy)-4-methylpyridin-2-yl)oxy]-benzamidine,Trifluoroacetic Acid Salt

[1194] A. To3-[(3,5-difluoro-4-methyl-6-(3-((phenyl)oxomethyl)phenoxy)-pyridin-2-yl)oxy]benzamidine,acetic acid salt, (0.10 g, 0.19 mmol) in methanol was added Pd-C (75mg). After stirring under hydrogen for 2.5 hours, the reaction wasfiltered, concentrated in vacuo, and purified by HPLC as described abovein Example 5 to give 3-[(3,5-difluoro-6-(3-((phenyl)hydroxymethyl)phenoxy)-4-methyl-pyridin-2-yl)oxy]benzamidinetrifluoroaceticacidsalt; NMR (DMSO-d₆) 9.45 (s,2), 9.35(s,2), 7.55 (m,4), 7.1-7.4 (m,8), 6.95 (m,1), 5.64 (s,1), 2.4 (s,3) ppm.

EXAMPLE 144-Hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-imino-ethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,Trifluoroacetic Acid Salt

[1195] A. To ethanol (8 mL) was added

[1196]4-hydroxy-3-[(3,5-dichloro-6-(3-dimethyl-aminocarbonylphenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy)benzamidine(0.16 g, 0.20 mmol), ethylacetimidate hydrochloride (74 mg, 0.6 mmol),and triethylamine (0.10 g, 1.0 mmol). After stirring for 2 hours, thereaction mixture was concentrated and purified by HPLC as describedabove in Example 5 to give4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonyl-phenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

[1197] B. In a similar manner, the following compounds were made:

[1198]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

[1199]4-hydroxy-3-l(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

[1200]4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt 6922.

[1201] C. In a similar manner, the following compounds are made:

[1202]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-iminoethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

[1203]4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(1-iminoethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

[1204]4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(1-iminoethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

EXAMPLE 15

[1205] This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine:A. Ingredients % wt./wt. Compound of the invention 20.0% Lactose 79.5%Magnesium stearate  0.5%

[1206] The above ingredients are mixed and dispensed into hard-shellgelatin capsules containing 100 mg each. B. Ingredients % wt./wt.Compound of the invention 20.0%  Magnesium stearate 0.9% Starch 8.6%Lactose 79.6%  PVP (polyvinylpyrrolidine) 0.9%

[1207] The above ingredients with the exception of the, magnesiumstearate are combined and granulated using water as a granulatingliquid. The formulation is then dried, mixed with the magnesium stearateand formed into tablets with an appropriate tableting machine. C.Ingredients Compound of the invention 0.1 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80 1.0 g Water q.s. 100 mL

[1208] The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled. D. Ingredients % wt./wt. Compound of theinvention 20.0% Peanut Oil 78.0% Span 60 2.0%

[1209] The above ingredients are melted, mixed and filled into softelastic capsules. E. Ingredients % wt./wt. Compound of the invention1.0% Methyl or carboxymethyl cellulose 2.0% 0.9% saline q.s. 100 mL

[1210] The compound of the invention is dissolved in thecellulose/saline solution, filtered and bottled for use.

EXAMPLE 16

[1211] This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]-benzamidine:Ingredients Compound of the invention 0.02 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80  1.0 g 0.9% Salinesolution q.s. 100 mL

[1212] The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2 p membrane filter andpackaged under sterile conditions.

EXAMPLE 17

[1213] This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methyl-imidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylmethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine:Ingredients % wt./wt. Compound of the invention  1.0% Polyethyleneglycol 1000 74.5% Polyethylene glycol 4000 24.5%

[1214] The ingredients are melted together and mixed on a steam bath,and poured into molds containing 2.5 g total weight.

EXAMPLE 18

[1215] This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)-pyridin-2-yl)oxy]benzamidine:Ingredients % wt./wt. Micronized compound of the invention  1.0%Micronized lactose 99.0%

[1216] The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 19

[1217] This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)-oxy]benzamidine:Ingredients % wt./wt. Compound of the invention  0.005% Water 89.995%Ethanol 10.000%

[1218] The compound of the invention is dissolved in ethanol and blendedwith water. The formulation is then packaged in a nebulizer equippedwith a dosing pump.

EXAMPLE 20

[1219] This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine:Ingredients % wt./wt. Compound of the invention 0.10% Propellant 11/1298.90%  Oleic acid 1.00%

[1220] The compound of the invention is dispersed inoleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

EXAMPLE 21 In vitro assay for Factor Xa, Thrombin and Tissue PlasminogenActivator

[1221] This assay demonstrates the activity of the compounds of theinvention towards factor Xa, thrombin and tissue plasminogen activator.The activities were determined as an initial rate of cleavage of thepeptide p-nitroanilide by the enzyme. The cleavage product,p-nitroaniline, absorbs at 405 nm with a molar extinction coefficient of9920 M⁻¹cm⁻¹.

[1222] Reagents and Solutions

[1223] Dimethyl sulfoxide (DMSO) (Baker analyzed grade).

[1224] Assay buffer:

[1225] 50 mM TrisHCl, 150 mM NaCI, 2.5 mM CaCl₂, and 0.1% polyethyleneglycol 6000, pH 7.5.

[1226] Enzymes (Enzyme Research Lab.):

[1227] 1. Human factor Xa stock solution: 0.281 mg/mL in assay buffer,stored at −80° C. (working solution (2X): 106 ng/mL or 2 nM in assaybuffer, prepare prior to use).

[1228] 2. Human thrombin stock solution: Stored at −80° C. (workingsolution (2X): 1200 ng/mL or 40 nM in assay buffer, prepare prior touse).

[1229] 3. Human tissue plasminogen activator (tPA) (Two chains, Sigma)stock solution: 1 mg/mL, stored at −80° C. (working solution (2X): 1361ng/mL in assay buffer, prepare prior to use).

[1230] Chromogenic substrates (Pharmacia Hepar Inc.):

[1231] 1. S2222 (FXa assay) stock solution: 6 mM in dH₂0, store at 4° C.(working solution (4X): 656 pyM in assay buffer).

[1232] 2. S2302 (Thrombin assay) stock solution: 10 mM in dH₂O, storedat 4° C. (working solution (4X): 1200 yM in assay buffer).

[1233] 3. S2288 (tPA assay) stock solution: 10 mM in dH₂0, stored at 4°C. (working solution (4X): 1484 yM in assay buffer).

[1234] (All substrate working solutions were prepared on assay day 5.)

[1235] Standard inhibitor compound stock solution:

[1236] 5 mM in DMSO, stored at −20° C.

[1237] Test compounds (compounds of the invention) stock solutions:

[1238] 10 mM in DMSO, stored at −20° C.

[1239] Assay Procedure

[1240] Assays were performed in 96-well microtiter plates in a totalvolume of 200 μl. Assay components were in final concentration of 50 mMTrisHCl, 150 mM NaCl, 2.5 mM CaCl₂, 0.1% polyethylene glycol 6000, pH7.5, in the absence or presence of the standard inhibitor or the testcompounds and enzyme and substrate at following concentrations: (1) 1 nMfactor Xa and 164 ρM S2222; (2) 20 nM thrombin and 300 μM S2302; and (3)10 nM tPA and 371 μM S2288.

[1241] Concentrations of the standard inhibitor compound in the assaywere from 5 μM to 0.021 μM in 1 to 3 dilution. Concentration of the testcompounds in the assay typically were from 10 μM to 0.041 μM in 1 to 3dilution. For potent test compounds, the concentrations used in thefactor Xa assay were further diluted 100 fold (100 nM to 0.41 nM) or1000 fold (10 nM to 0.041 nM). All substrate concentrations used areequal to their K_(m) values under the present assay conditions. Assayswere performed at ambient temperature.

[1242] The first step in the assay was the preparation of 10 mM testcompound stock solutions in DMSO (for potent test compounds, 10 mM stocksolutions were further diluted to 0.1 or 0.01 mM for the factor Xaassay), followed by the preparation of test compound working solutions(4X) by a serial dilutions of 10 mM stock solutions with Biomek 1000 (orMultiprobe 204) in 96 deep well plates as follows:

[1243] (a) Prepare a 40 μM working solution by diluting the 10 mM stock1 to 250 in assay buffer in 2 steps: 1 to 100, and 1 to 2.5.

[1244] (b) Make another five serial dilutions (1:3) of the 40 μMsolution (600 μl for each concentration). A total of six diluted testcompound solutions were used in the assay. Standard inhibitor compound(5 mM stock) or DMSO (control) went through the same dilution steps asthose described above for test compounds.

[1245] The next step in the assay was to dispense 50 μl of the testcompound working solutions (4X) (from 40 uM to 0.164 uM) in duplicate tomicrotiter plates with Biomek or MP204. To this was added 100 μl ofenzyme working solution (2X) with Biomek or MP204. The resultingsolutions were incubated at ambient temperature for 10 minutes.

[1246] To the solutions was added 50 μl of substrate working solution(4X) with Biomek or MP204.

[1247] The enzyme kinetics were measured at 405 nm at 10 secondsintervals for five minutes in a THERMOmax plate reader at ambienttemperature.

[1248] Calculation of K_(i) of the Test Compounds

[1249] Enzyme rates were calculated as mOD/min based on the first twominutes readings. The lC₅₀ values were determined by fitting the data tothe log-logit equation (linear) or the Morrison equation (non-linear)with an EXCEL spread-sheet. Ki values werethen obtained by dividing theIC₅₀ by 2. Routinely, Ki(factor Xa) values less than 3 nM werecalculated from the Morrison equation.

[1250] Compounds of the invention, when tested in this assay,demonstrated the selective ability to inhibit human factor Xa and humanthrombin.

EXAMPLE 22 In vitro assay for Human Prothrombinase

[1251] This assay demonstrates the ability of the compounds of theinvention to inhibit prothrombinase. Prothrombinase (PTase) catalyzesthe activation of prothrombin to yield fragment 1.2 plus thrombin withmeizothrombin as the intermediate. This assay is an end point assay.Activity of the prothrombinase is measured by activity of thrombin (oneof the reaction products) or by the amount of thrombin formed/time basedon a thrombin standard curve (nM vs mOD/min). For determination of IC₅₀(PTase) of the compounds of the invention, PTase activity was expressedby thrombin activity (mOD/min). pos Materials

[1252] Enzymes

[1253] 1. Human factor Va (Haematologic Technologies Inc., Cat#HCVA-0110) working solution: 1.0 mg/mL in 50% glycerol, 2 mM CaCl₂,stored at −20° C.

[1254] 2. Human factor Xa (Enzyme Res. Lab. cat# HFXal011) workingsolution: 0.281 mg/mL in assay buffer (without BSA), stored at −80° C.

[1255] 3. Human prothrombin (FII) (Enzyme Res. Lab., Cat# HP1002)working solution:

[1256] Diluted FlI to 4.85 mg/mL in assay buffer (without BSA), storedat −80° C.

[1257] Phospholipid (PCPS) vesicles:

[1258] PCPS vesicles (80% PC, 20% PS) were prepared by modification ofthe method reported by Barenholz et al., Biochemistry (1977), Vol. 16,pp. 2806-2810.

[1259] Phosphatidyl serine (Avanti Polar Lipids, Inc., Cat#840032):

[1260] 10 mg/mL in chloroform, purified from brain, stored −20° C. undernitrogen or argon.

[1261] Phosphatidyl Choline (Avanti Polar Lipids, Inc., Cat# 850457):

[1262] 50 mg/ml in chloroform, synthetic 16:0-18:1 Palmitoyl—Oleoyl,stored at −20° C. under nitrogen or argon.

[1263] Spectrozyme-TH (American Diagnostica Inc., Cat# 238L, 50 ,moles,stored at room temperature) working solution: Dissolved 50 ,moles in 10mL dH₂O.

[1264] BSA (Sigma Chem Co., Cat# A−7888, FractionV, RIA grade).

[1265] Assay buffer: 50 mM TrisHCl, pH 7.5, 150 mM NaCl, 2.5 mM CaCl₂,0.1% PEG 6000 (BDH), 0.05% BSA (Sigma, Fr.V, RIA grade).

[1266] For one plate assay, preparethe following working solutions:

[1267] 1. Prothrombinase complex:

[1268] (a) 100 μM PCPS (27.5 μl of PCPS stock (4.36 mM) diluted to final1200 μl with assay buffer.

[1269] (b) 25 nM Human factor Va: 5.08 μl of Va stock(1 mg/mL) wasdiluted to final 1200 μl with assay buffer.

[1270] (c) 5 pM Human factor Xa: Dilute Xa stock (0.281 mg/mL)1:1,220,000 with assay buffer. Prepare at least 1200 μl .

[1271] Combine equal volumes (1100 μl) of each component in the order ofPCPS, Va and Xa. Let stand at ambient temperature for 5 to 10 minutesand use immediately or store in ice (bring to ambient temperature beforeuse).

[1272] 2. 6 μM Human prothrombin (FII): dilute 124 μL of FlI stock (4.85mg/mL) to final 1400 μL with assay buffer.

[1273] 3. 20 mM EDTA/Assay buffer: 0.8 mL of 0.5M EDTA (pH 8.5) plus19.2 mL assay buffer.

[1274] 4. 0.2 mM Spectrozyme-TH/EDTA buffer: 0.44 mL of SPTH stock (5mM) plus 10.56 mL of 20 mM EDTA/assay buffer.

[1275] 5. Test compounds (compounds of the invention):

[1276] Prepare a working solution (5X) from 10 mM stock (DMSO) and makea series of 1:3 dilution. Compounds were assayed at 6 concentrations induplicate.

[1277] Assay Conditions and Procedure

[1278] Prothrombinase reaction was performed in final 50 μL of mixturecontaining PTase (20 uM PCPS, 5 nM hFVa, and 1 pM hFXa), 1.2 uM humanfactor 11 and varied concentration of the test compounds (5 μM to 0.021μM or lower concentration rarige). Reaction was started by addition ofPTase and incubated for 6 minutes at room temperature. Reaction wasstopped by addition of EDTA/buffer to final 10 mM. Activity of thrombin(product) was then measured in the presence of 0.1 mM of Spectrozyme-THas substrate at 405 nm for 5 minutes (10 seconds intervals) at ambienttemperature in a THEROmax microplate reader. Reactions were performed in96-well microtiter plates.

[1279] In the first step of the assay, 10 μl of diluted test compound(5X) or buffer was added to the plates in duplicate. Then 10 μl ofprothombin (hFII) (5X) was added to each well. Next 30 μl PTase wasadded to each well, mix for about 30 seconds. The plates werethenincubated at ambient temperature for 6 minutes.

[1280] In the next step, 50 μl of 20 mM EDTA (in assay buffer) was addedto each well to stop the reaction. The resulting solutions werethenmixed for about 10 seconds. Then 100 μl of 0.2 mM spectrozyme was addedto each well. Thethrombin reaction rate was then measured at 405 nm for5 minutes at 10 seconds intervals in a Molecular Devices microplatereader.

[1281] Calculations

[1282] Thrombin reaction rate was expressed as mOD/miri. using ODreadings from the five minute reaction. IC₅₀ values were calculated withthe log-logit curve fit program.

[1283] The compounds of the invention demonstrated the ability toinhibit pro-thrombinase when tested in this assay.

EXAMPLE 23 In Vivo Assay

[1284] The following assay demonstrates the ability of the compounds toact as anti-coagulants.

[1285] Male rats (250-330 g) were anesthetized with sodium pentobarbital(90 mg/kg, i.p.) and prepared for surgery. The left carotid artery wascannulated for the measurement of blood pressure as well as for takingblood samples to monitor clotting variables (prothrombin time (PT) andactivated partial thromboplastin time (aPTT)). The tail vein wascannulated for the purpose of administering the test compounds (i.e.,the compounds of the invention and standards) and thethromboplastininfusion. The abdomen was opened via a mid-line incision and theabdominal vena cava was isolated for 2-3 cm distal to the renal vein.All venous branches in this 2-3 cm segment of the abdominal vena cavawere ligated. Following all surgery, the animals were allowed tostabilize prior to beginning the experiment. Test compounds wereadministered as an intravenous bolus (t=0). Three minutes later (t=3), a5-minute infusion of thromboplastin was begun. Two minutes into theinfusion (t=5), the abdominal vena cava was ligated at both the proximaland distal ends. The vessel was left in place for 60 minutes, afterwhich it was excised from the animal, slit open, the clot (ifany)carefully removed, and weighed. Statistical analysis on the resultswas perfomed using a Wilcoxin-matched-pairs signed rank test.

[1286] The compounds of the invention, when tested in this assay,demonstrated the ability to clot the blood and to inhibit the clottingof the blood.

[1287] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the.true spirit and scope of theinvention. In addition, many modifications may be made and equivalentsmay be substituted without departing from the true spirit and scope ofthe invention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound selected from the group consisting ofthe following formulae:

wherein A is —C(R¹¹)═or —N═; Z¹ and Z² are independently —O—, —N(R⁸)—,—S—, or —OCH₂—; R¹ and R³ are independently hydrogen, halo, alkyl,haloalkyl, alkoxy, haloalkoxy, nitro, —N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹,—C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸,—N(R⁸)S(O)₂R¹², or —N(R⁸)C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹; R² is hydrogen; halo;alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸; —C(O)N(R⁸)R⁹; —N(R⁸)R⁹;—C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3); —N(R⁸)(CH₂)_(n)C(O)OR⁸(where n is 1 to 3); —N((CH₂)_(m)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each nis 1 to 3); —O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3);—O(CH₂)_(p)C(O)OR⁸ (where p is 1 to 6);—N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n is independently1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy; or R² is aryloxy(optionally substituted by one or more substituents independentlyselected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹, halo, alkyl,carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is 1-piperazinoyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is piperidin-1-yl(optionally substituted by one or more substituents selected from thegroup consisting of carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl,and alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of alkylcarbonyl, carboxy, —C(O)N(R⁸)R⁹, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, —C(O)N(R⁸)R⁹, alkoxycarbonylalkyl andaralklyl); or R² is 3-pyrrolidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R⁸)R⁹,alkoxycarbonyl and alkoxycarbonylalkyl); R⁴ and R⁷ are independentlyhydrogen, halo, alkyl, nitro, —OR⁸, —C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹,—N(H)C(O)R⁸, or —N(H)S(O)₂R¹²; R⁵ is —C(NH)NH₂, —C(NH)N(H)OR⁸,—C(NH)N(H)C(O)OR¹ ², —C(NH)N(H)S(O)₂R¹², —C(NH)N(H)C(O)N(R⁸)R⁹, or—C(NH)N(H)C(O)R⁸; R⁶ is halo, alkyl, haloalkyl, haloalkoxy, nitro,amino, ureido, guanidino, —OR⁸ ₁ —C(NH)NH₂, —C(NH)NHOH, —C(O)R¹⁰,—(CH₂)_(m)C(O)N(R⁸)R⁹ (where m is 0 to 3), —CH(OH)C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3), —(CH₂)_(m)C(O)OR⁸ (where m is 0to 3), —N(H)C(O)R⁸, (1,2)-tetrahydropyrimidinyl (optionally substitutedby alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ areindependently hydrogen, alkyl, aryl, or aralkyl; R¹⁰ is hydrogen, alkyl,aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl,4-(N-methyl)piperazinyl, or piperidin-1-yl; R¹¹ is hydrogen, alkyl orhalo; and R¹² is alkyl, aryl or aralkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound selected from formula (I):

wherein A is —N═; Z¹ and Z² are independently —O—, —N(R⁸)— or —OCH₂—; R¹and R³ are independently hydrogen, fluoro, chloro, haloalkyl, —N(R⁸)R⁹,—C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸, or—N(R⁸)S(O)₂R¹²; R² is hydrogen; halo; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸;—C(O)N(R⁸)R⁹; —N(R⁸)R⁹; —C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3);—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);—N((CH₂)_(n)N(R⁸)R⁹)(CH₂),C(O)OR⁸ (where each n is 1 to 3);—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy; or R² isaryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹,halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is 1-piperazinoyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R²is piperidin-1-yl(optionally substituted by one or more substituents selected from thegroup consisting of carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl,or alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of alkylcarbonyl, carboxy, —C(O)N(R⁸)R⁹, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl, or tetrazolylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, —C(O)N(R⁸)R⁹, alkoxycarbonylalkyl oraralklyl); or R² is 3-pyrrolidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R⁸)R⁹,alkoxycarbonyl or alkoxycarbonylalkyl); R⁴ is hydrogen, —OR⁸ or—N(R⁸)R⁹; R⁵ is —C(NH)NH₂; R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹,—CH(OH)C(O)N(R⁸)R⁹, —(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3),1-piperidinoyl, 1-pyrrolidinoyl, (1,2)-imidazolyl (optionallysubstituted by alkyl), or (1,2)-imidazolinyl (optionally substituted byalkyl); R⁷ is hydrogen, halo, alkyl, —OR⁸, —C(O)N(R⁸)R⁹; R⁸ and R⁹ areindependently hydrogen, methyl, ethyl or phenyl; and R¹² is methyl,ethyl, phenyl or benzyl.
 3. The compound of claim 2 wherein Z¹ and Z²are independently —O— or —NCH₃—; R¹ and R³ are independently hydrogen,fluoro, chloro, trifluoromethyl, amino, —C(O)N(R⁸)R⁹, or —NHC(O)NHR⁹; R²is hydrogen; halo; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸; —N(R⁸)R⁹;—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);-N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3);—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy; or R² isaryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹,halo, alkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, tetrazolyl, morpholin-4-ylalkyl,and (1,2)-imidazolinyl (optionally substituted by alkyl)); or R² ispiperazin-1-yl (optionally substituted by one or more substituentsindependently selected from the group consisting of alkyl, carboxyalkyl,and alkoxycarbonylalkyl); or R² is piperidin-1-yl (optionallysubstituted by one or more substituents selected from the groupconsisting of carboxy and alkoxycarbonyl); or R² is (3,4)-piperidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of carboxyalkyl and alkoxycarbonylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of carboxyalkyl,alkoxycarbonylalkyl and aralklyl); or R² is 3-pyrrolidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyland alkoxycarbonylalkyl); R⁴ is hydrogen, amino, hydroxy, or methoxy; R⁵is —C(NH)NH₂; R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 1), (1,2)-imidazolyl substituted byalkyl, or 2-imidazolinyl substituted by alkyl; R⁷ is hydrogen, methoxy,or hydroxy; and R⁸ and R⁹ are independently hydrogen, methyl, ethyl, orphenyl.
 4. The compound of claim 3 wherein Z¹ and Z² are both —O—; R¹and R³ are independently hydrogen, fluoro, or chloro; R⁴ is amino,hydrogen, hydroxy or methoxy; R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 or 1), (1,2)-imidazolyl substituted bymethyl, or 2-imidazolinyl optionally substituted by methyl; and R⁷ ishydrogen or hydroxy.
 5. The compound of claim 4 wherein R⁴ is hydroxy;R⁶ is dimethylamino or dimethylaminocarbonyl; and R⁷ is hydrogen.
 6. Thecompound of claim 5 selected from the group consisting of the following:4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonyl-methylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-propoxy-pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-1(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-dimethylamino-pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,2,2-trifluoro-ethoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-bromo-3-fluoro-prop-2-oxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethyl aminocarbonylphenoxy)-4-methoxy-pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxymethyl-piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-1-yl)-pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-1(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(morpholin-4-yl)-pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxymethyl-piperazinyl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonyl-methylpiperazinyl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-l(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-(morpholin-4-ylmethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-carboxy-methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-carboxymethoxypyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-dimethyl-aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl]oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonyl-methylpyrrolidin-3-yloxy)pyridin-2-yl]oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;and4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)-((carboxymethyl)aminocarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine.7. The compound of claim 4 wherein R⁴ is hydroxy; R⁶ is (1,2)-imidazolylsubstituted by methyl or 2-imidazolinyl substituted by methyl; and R⁷ ishydrogen.
 8. The compound of claim 7 selected from the group consistingof the following:4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-phenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)-(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)-(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-1(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(methoxy-carbonyl)ethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(l1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-4-(3-(1-methylimidazolin-2-yl)phenoxy)-6-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(2-methoxy-4-carboxy-phenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxycarbonylmethyl) piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(ethoxycarbonylmethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)qoxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-ethoxy-carbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-dimethyl-aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxy-methylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxy-carbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(ethoxycarbonyl-methyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzyl-piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)-(methyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzyl-piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;and4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine.9. The compound of claim 4 wherein R⁴ is hydroxy; R⁶ is guanidino; andR⁷ is hydrogen.
 10. The compound of claim 9 selected from the groupconsisting of the following:4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-ethoxycarbonylmethyl-piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-12,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yloxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-dimethoxy-4aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)-pyridin-2-yl) oxy]benzamidine; and 4-hydroxy-3-[(3,5 5-diflIuoro-6-(3-(guanidino)phenoxy)-4-(4-carboxy-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine.11. The compound of claim 1 which is selected from formula (VII):

wherein Z¹ and Z² are independently —O—, —N(R⁸)—or —OCH₂—; R¹ and R³ areindependently hydrogen, fluoro, chloro, haloalkyl, —N(R⁸)R⁹, —C(O)OR⁸,—C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸, or —N(R⁸)S(O)₂R¹²; R² ishydrogen; halo; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸; —C(O)N(R⁸)R⁹;—N(R⁸)R⁹; —C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3);—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);—N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3);—O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where pis 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂),C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy; or R² isaryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹,halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is 1-piperazinoyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is piperidin-1-yl(optionally substituted by one or more substituents selected from thegroup consisting of carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl,or alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of alkylcarbonyl, carboxy, —C(O)N(R⁸)R⁹, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl, or tetrazolylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, —C(O)N(R⁸)R⁹, alkoxycarbonylalkyl oraralklyl); or R² is 3-pyrrolidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R⁸)R⁹,alkoxycarbonyl or alkoxycarbonylalkyl); R⁴ is hydrogen, —OR⁸ or—N(R⁸)R⁹; R⁵ is —C(NH)NH₂; R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹,—CH(OH)C(O)N(R⁸)R⁹, —(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3),1-piperidinoyl, 1-pyrrolidinoyl, (1,2)-imidazolyl (optionallysubstituted by alkyl), or (1,2)-imidazolinyl (optionally substituted byalkyl); R⁷ is hydrogen, halo, alkyl, —OR⁸, —C(O)N(R⁸)R⁹; R⁸ and R⁹ areindependently hydrogen, methyl, ethyl or phenyl; and R¹² is methyl,ethyl, phenyl or benzyl.
 12. The compound of claim 11 wherein Z¹ and Z²are independently —O— or —NCH₃—; R¹ and R³ are independently hydrogen,fluoro, chloro, trifluoromethyl, amino, —C(O)N(R⁸)R⁹, or —NHC(O)NHR⁹; R²is hydrogen; halo; alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸; —N(R⁸)R⁹;—N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n is 1 to 3);-N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n)C(O)OR⁸ (where each n is 1 to 3); —O(CH₂)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸ (where p is 1 to 6);—N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (where each n is independently1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy; or R² is aryloxy(optionally substituted by one or more substituents independentlyselected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹, halo, alkyl,carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, tetrazolyl, morpholin-4-ylalkyl,and (1,2)-imidazolinyl (optionally substituted by alkyl)); or R² ispiperazin-1-yl (optionally substituted by one or more substituentsindependently selected from the group consisting of alkyl, carboxyalkyl,and alkoxycarbonylalkyl); or R² is piperidin-1-yl (optionallysubstituted by one or more substituents selected from the groupconsisting of carboxy and alkoxycarbonyl); or R² is (3,4)-piperidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of carboxyalkyl and alkoxycarbonylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of carboxyalkyl,alkoxycarbonylalkyl and aralklyl); or R² is 3-pyrrolidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyland alkoxycarbonylalkyl); R⁴ is hydrogen, amino, hydroxy, or methoxy; R⁵is —C(NH)NH₂; R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 1), (1,2)-imidazolyl substituted byalkyl, or 2-imidazolinyl substituted by alkyl; R⁷ is hydrogen, methoxy,or hydroxy; and R⁸ and R⁹ are independently hydrogen, methyl, ethyl, orphenyl.
 13. The compound of claim 12 wherein Z¹ and Z² are both —O—; R¹and R³ are independently hydrogen, fluoro, or chloro; R⁴ is hydrogen,amino, hydroxy or methoxy; R⁶ is guanidino, —C(NH)NH₂, —C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 or 1), (1,2)-imidazolyl substituted bymethyl, or 2-imidazolinyl optionally substituted by methyl; and R⁷ ishydrogen or hydroxy.
 14. The compound of claim 13 wherein R⁴ is hydroxy;R⁶ is dimethylamino or dimethylaminocarbonyl; and R⁷ is hydrogen. 15.The compound of claim 14 selected from the group consisting of thefollowing:4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-methoxy-pyridin-4-yl)oxy]benzamidine;and4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-4-yl)oxy]benzamidine.16. A pharmaceutical composition useful in treating a human having adisease-state characterized by thrombotic activity, which compositioncomprises a therapeutically effective amount of a compound selected fromthe group consisting of the following formulae:

wherein A is —C(R¹¹)═ or —N═; Z¹ and Z² are independently —O—, —N(R⁸)—,—S—, or —OCH₂—; R¹ and R³ are independently hydrogen, halo, alkyl,haloalkyl, alkoxy, haloalkoxy, nitro, —N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹,—C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸,—N(R⁸)S(O)₂R¹², or —N(R⁸)C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹; R² is hydrogen; halo;alkyl; haloalkoxy; —OR⁸; —C(O)OR“; —C(O)N(R⁸)R⁹; —N(R⁸)R⁹;—C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3); —N(R⁸)(CH₂)_(n)C(O)OR⁸(where n is 1 to 3); —N((CH₂)_(n)N(R⁸)R⁹)(CH₂),C(O)OR⁸ (where each n is1 to 3); —O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸(where p is 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸) (CH₂)_(p)C(O)OR⁸ (whereeach n is independently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹,halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbQnylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is 1-piperazinoyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is piperidin-1-yl(optionally substituted by one or more substituents selected from thegroup consisting of carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl,and alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of alkylcarbonyl, carboxy, —C(O)N(R⁸)R⁹, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, —C(O)N(R⁸)R⁹, alkoxycarbonylalkyl andaralklyl); or R² is 3-pyrrolidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R⁸)R⁹,alkoxycarbonyl and alkoxycarbonylalkyl); R⁴ and R⁷ are independentlyhydrogen, halo, alkyl, nitro, —OR⁸, —C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹,—N(H)C(O)R⁸, or —N(H)S(O)₂R¹²; R⁵ is —C(NH)NH₂, —C(NH)N(H)OR⁸,—C(NH)N(H)C(O)OR¹², —C(NH)N(H)S(O)₂R¹², —C(NH)N(H)C(O)N(R⁸)R⁹, or—C(NH)N(H)C(O)R⁸; R⁶ is halo, alkyl, haloalkyl, haloalkoxy, nitro,amino, ureido, guanidino, —OR⁸, —C(NH)NH₂, —C(NH)NHOH, —C(O)R¹⁰,—(CH₂)_(m)C(O)N(R⁸)R⁹ (where m is 0 to 3), —CH(OH)C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3), —(CH₂)_(m)C(O)OR⁸ (where m is 0to 3), —N(H)C(O)R⁸, (1,2)-tetrahydropyrimidinyl (optionally substitutedby alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ areindependently hydrogen, alkyl, aryl, or aralkyl; R¹⁰ is hydrogen, alkyl,aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl,4-(N-methyl)piperazinyl, or piperidin-1-yl; R¹¹ is hydrogen, alkyl orhalo; and R¹² is alkyl, aryl or aralkyl; or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipientthereof.
 17. A method of treating a human having a disease-statecharacterized by thrombotic activity, which method comprisesadministering to a human in need thereof a therapeutically effectiveamount of a compound selected from the group consisting of the followingformulae:

wherein A is —C(R¹¹)═ or —N═; Z¹ and Z² are independently —O—, —N(R⁸)—,—S—, or —OCH₂—; R¹ and R³ are independently hydrogen, halo, alkyl,haloalkyl, alkoxy, haloalkoxy, nitro, —N(R⁸)R⁹, —C(O)OR⁸, —C(O)N(R⁸)R⁹,—C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, —N(R⁸)C(O)N(R⁸)R⁹, —N(R⁸)C(O)R⁸,—N(R⁸)S(O)₂R¹², or —N(R⁸)C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹; R² is hydrogen; halo;alkyl; haloalkoxy; —OR⁸; —C(O)OR⁸; —C(O)N(R⁸)R⁹; —N(R⁸)R⁹;—C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3); —N(R⁸)(CH₂)_(n)C(O)OR⁸(where n is 1 to 3); —N((CH₂)_(n)N(R⁸)R⁹)(CH₂),C(O)OR⁸ (where each n is1 to 3); —O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); —O(CH₂)_(p)C(O)OR⁸(where p is 1 to 6); —N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n)C(O)OR⁸ (whereeach n is independently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of —OR⁸, —C(O)N(R⁸)R⁹,halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is 1-piperazinoyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is piperidin-1-yl(optionally substituted by one or more substituents selected from thegroup consisting of carboxy, —C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl,and alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of alkylcarbonyl, carboxy, —C(O)N(R⁸)R⁹, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R² ispiperidin-4-ylamino (wherein the amino is optionally substituted byalkyl and the piperidinyl group is optionally substituted by one or moresubstituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, —C(O)N(R⁸)R⁹, alkoxycarbonylalkyl andaralklyl); or R² is 3-pyrrolidinyloxy (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, —C(O)N(R⁸)R⁹,alkoxycarbonyl and alkoxycarbonylalkyl); R⁴ and R⁷ are independentlyhydrogen, halo, alkyl, nitro, —OR⁸, —C(O)OR⁸, —C(O)N(R⁸)R⁹, —N(R⁸)R⁹,—N(H)C(O)R⁸, or —N(H)S(O)₂R¹²; R⁵ is —C(NH)NH₂, —C(NH)N(H)OR⁸,—C(NH)N(H)C(O)OR¹², —C(NH)N(H)S(O)₂R¹², —C(NH)N(H)C(O)N(R⁸)R⁹, or—C(NH)N(H)C(O)R⁸; R⁶ is halo, alkyl, haloalkyl, haloalkoxy, nitro,amino, ureido, guanidino, —OR⁸, —C(NH)NH₂, —C(NH)NHOH, —C(O)R¹⁰,—(CH₂)_(m)C(O)N(R⁸)R⁹ (where m is 0 to 3), —CH(OH)C(O)N(R⁸)R⁹,—(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3), —(CH₂)_(m)C(O)OR⁸ (where m is 0to 3), —N(H)C(O)R⁸, (1,2)-tetrahydropyrimidinyl (optionally substitutedby alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ areindependently hydrogen, alkyl, aryl, or aralkyl; R¹⁰ is hydrogen, alkyl,aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl,4-(N-methyl)piperazinyl, or piperidin-1-yl; R¹⁰ is hydrogen, alkyl orhalo; and R¹² is alkyl, aryl or aralkyl; or a pharmaceuticallyacceptable salt thereof.